Tag: Cell

New trials show promise for immune checkpoint blockers in early-stage lung cancer

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In a recent phase I trial published in the journal Cell Reports Medicine, researchers from Belgium administered a dendritic cell (DC) vaccine targeting patient-specific neoantigens to patients with resected non-small cell lung cancer (NSCLC).

They found that the vaccine was viable and led to limited toxicity and systemic T-cell responses, with 50% of patients experiencing disease recurrence during the study.

Study: Neoantigen-targeted dendritic cell vaccination in lung cancer patients induces long-lived T cells exhibiting the full differentiation spectrum. Image Credit: PhotobyTawat/Shutterstock.com

Background

NSCLC, constituting over 80% of lung cancer cases, is primarily treated with surgical resection in early stages, yet recurrence rates remain high, with highly variable 5-year survival rates.

Adjuvant chemotherapy offers modest survival benefits and often impacts the quality of life severely, emphasizing the need for more efficacious and tolerable adjuvant therapies. Recent phase 3 trials showed that immune checkpoint blockers (ICBs) benefit high-risk early-stage NSCLC, improving disease-free survival, but concerns exist over their toxicity.

Neoantigen-targeting vaccines are extensively researched across different cancer stages, showing promising outcomes by inducing robust, high-affinity T-cell responses. Trials confirm their feasibility, safety, and potential clinical benefits, alone or combined with ICBs.

DCs are highly efficient antigen-presenting cells, widely studied for cancer vaccination. However, their clinical efficacy is limited, partially due to their emphasis on tumor-associated antigens instead of mutanome-derived neoantigens.

Therefore, in the present study, researchers investigated the safety and efficacy of an autologous DC vaccine targeting neoantigens for the treatment of resected NSCLC patients.

About the study

The study recruited ten resectable NSCLC patients without specific gene mutations in stages Ia3–IVb. Tumor material and peripheral blood samples were collected for whole-exome sequencing (WES) and ribonucleic acid (RNA) sequencing.

A neoantigen identification pipeline was developed, prioritizing clonal variants with strong predicted binding to human leukocyte antigen (HLA) class I allotypes and RNA expression.

Neoepitopes were selected based on their absence from the healthy human proteome and immunogenic potential. Mass spectrometry (MS)–based immuno-peptidomics, cell line engineering, and tumor-infiltrating lymphocyte (TIL) reactivity analyses were employed for neoantigen validation.

Six patients received intravenous administrations of messenger RNA (mRNA)-loaded monocyte-derived DCs (Neo-mDCs) and were monitored for safety and clinical activity. The median time from surgery to the first vaccination was 198 days.

Peripheral blood mononuclear cells (PBMCs) from patients receiving Neo-mDC treatment were analyzed for CD4+ and CD8+ T-cell responses against neoantigen 25-mers using interferon-gamma (IFN-γ) staining after in vitro stimulation.

The correlation between T-cell responses and the detection of tandem protein in Neo-mDC batches was assessed. PBMCs were also analyzed to assess ex vivo T-cell frequency and differentiation phenotype.

Individual clonotypes within neoantigen-specific T-cell populations were examined through single-cell analysis of the T-cell receptor (TCR) repertoire in tetramer-positive cells.

Results and discussion

Seven out of nine patients had five to six neoantigens selected for vaccination, with 0–56 potential neoepitopes identified per patient. Validation analyses confirmed that nine out of 33 selected neoantigens were naturally processed and presented on tumor HLA, supporting the reliability of the identification approach.

Adverse events (AEs) were mild and self-limiting, with no grade 3–4 AEs reported. While three patients experienced disease recurrence, three patients remained free of disease recurrence during the follow-up period.

Five out of six treated patients exhibited vaccine-induced T-cell responses, with 14 out of 33 neoantigens-inducing responses. Most responses were CD8+ T-cell-mediated and emerged after the first dose, persisting throughout treatment.

Even at low doses, Neo-mDCs primed naive T-cells and/or expanded pre-existing T-cell responses.

However, T-cell responses did not always correlate with detecting tandem protein in Neo-mDC batches. CD8+ T cell responses were highly specific for predicted neoepitopes, with no cross-reactivity observed toward wild-type epitopes. These results highlight the immunogenic potential of Neo-mDC vaccination in NSCLC patients.

Post-vaccination, tetramer-positive T-cells expanded and were found to persist for ≥1.5 years. Analysis revealed naive, early, and late differentiated T-cell clusters with tetramer-positive cells across these states.

These findings demonstrate the induction of diverse, long-lived neoantigen-specific T-cell responses by Neo-mDC vaccination in NSCLC patients.

Further, the T-cells induced by vaccination included effector and long-lasting cells that could persist for several years. The T-cell populations generated by the vaccine were diverse and polyclonal, consisting of multiple clonotypes that exhibited a wide range of differentiation states.

Overall, this first-in-human clinical trial provides valuable insights on using an autologous DC therapy delivering mRNA-encoded, patient-specific tumor neoantigens in NSCLC patients. However, it is limited by its small patient cohort and prolonged vaccine manufacturing time.

Conclusion

In conclusion, the study demonstrated neoantigen-targeted autologous DC vaccination’s safety, feasibility, and immunogenicity in surgically resected NSCLC patients.

The findings highlight the potential of personalized immunotherapy strategies in combating NSCLC and possibly other malignancies to improve patient outcomes.

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April 18, 2024
Penn State study examines how a person’s telomeres are affected by caloric restriction

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Penn State researchers may have uncovered another layer of complexity in the mystery of how diet impacts aging. A new study led by researchers in the Penn State College of Health and Human Development examined how a person’s telomeres -; sections of genetic bases that function like protective caps at the ends of chromosomes -; were affected by caloric restriction.

The team published their results in Aging Cell. Analyzing data from a two-year study of caloric restriction in humans, the researchers found that people who restricted their calories lost telomeres at different rates than the control group -; even though both groups ended the study with telomeres of roughly the same length. Restricting calories by 20% to 60% has been shown to promote longer life in many animals, according to previous research.

Over the course of human life, every time a person’s cells replicate, some telomeres are lost when chromosomes are copied to the new cell. When this happens, the overall length of the cell’s telomeres becomes shorter. After cells replicate enough times, the protective cap of telomeres completely dissipates. Then, the genetic information in the chromosome can become damaged, preventing future reproduction or proper function of the cell. A cell with longer telomeres is functionally younger than a cell with short telomeres, meaning that two people with the same chronological age could have different biological ages depending on the length of their telomeres.

Typical aging, stress, illness, genetics, diet and more can all influence how often cells replicate and how much length the telomeres retain, according to Idan Shalev, associate professor of biobehavioral health at Penn State. Shalev led the researchers who analyzed genetic samples from the national CALERIE study -; the first randomized clinical trial of calorie restriction in humans. Shalev and his team sought to understand the effect of caloric restriction on telomere length in people. Because telomere length reflects how quickly or slowly a person’s cells are aging, examining telomere length could allow scientists to identify one way in which caloric restriction may slow aging in humans.

“There are many reasons why caloric restriction may extend human lifespans, and the topic is still being studied,” said Waylon Hastings, who earned his doctorate in biobehavioral health at Penn State in 2020 and was lead author of this study. “One primary mechanism through which life is extended relates to metabolism in a cell. When energy is consumed within a cell, waste products from that process cause oxidative stress that can damage DNA and otherwise break down the cell. When a person’s cells consume less energy due to caloric restriction, however, there are fewer waste products, and the cell does not break down as quickly.”

The researchers tested the telomere length of 175 research participants using data from the start of the CALERIE study, one year into the study and the end of the study after 24 months of caloric restriction. Approximately two-thirds of study participants participated in caloric restriction, while one-third served as a control group.

During the study, results showed that telomere loss changed trajectories. Over the first year, participants who were restricting caloric intake lost weight, and they lost telomeres more rapidly than the control group. After a year, the weight of participants on caloric restriction was stabilized, and caloric restriction continued for another year. During the second year of the study, participants on caloric restriction lost telomeres more slowly than the control group. At the end of two years, the two groups had converged, and the telomere lengths of the two groups was not statistically different.

This research shows the complexity of how caloric restriction affects telomere loss. We hypothesized that telomere loss would be slower among people on caloric restriction. Instead, we found that people on caloric restriction lost telomeres more rapidly at first and then more slowly after their weight stabilized.”

Idan Shalev, associate professor of biobehavioral health at Penn State

Shalev said the results raised a lot of important questions. For example, what would have happened to telomere length if data had been collected for another year? Study participants are scheduled for data collection at a 10-year follow-up, and Shalev said that he was eager to analyze those data when they become available.

Despite the ambiguity of the results, Shalev said there is promise for the potential health benefits of caloric restriction in humans. Previous research on the CALERIE data has demonstrated that caloric restriction may help reduce harmful cholesterol and lower blood pressure. For telomeres, the two-year timeline was not sufficient to show benefits, but those may still be revealed, according to Shalev and Hastings.

Three of Shalev’s trainees, Hastings, current graduate student Qiaofeng Ye and former postdoctoral scholar Sarah Wolf, led the research under Shalev’s guidance.

Hastings said the opportunity to lead this study was critical to his career.

“I was recently hired as an assistant professor in the Department of Nutrition at Texas A&M University, and I will begin that work in the fall semester,” Hastings said. “Prior to this project, I had limited experience in nutrition. This project literally set the course of my career, and I am grateful to Dr. Shalev for trusting me with that responsibility.”

Calen Ryan and Daniel Belsky of Columbia University Mailman School of Public Health, Sai Krupa Das of Tufts University, Kim Huffman and William Kraus of Duke University School of Medicine, Michael Kobor and Julia MacIsaac of University of British Columbia, Corby Martin and Leanne Redman of Pennington Biomedical Research Center and Susan Racette of Arizona State University College of Health Solutions all contributed to this research.

The National Institute on Aging funded this research.

Source:

Journal reference:

Hastings, W. J., et al. (2024). Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIETM 2 trial analysis. Aging Cell. doi.org/10.1111/acel.14149.

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April 18, 2024
New research pinpoints key pathways in prostate cancer’s vulnerability to ferroptosis
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In a recent review published in the journal Nature Reviews Urology, researchers examined the molecular mechanisms and metabolic processes that drive ferroptosis — a form of cell death that plays a significant role in prostate cancer. They also connected pathways involved in ferroptosis to the metabolic reprogramming that occurs in prostate cancer cells to highlight potential avenues of targeted therapeutic interventions.

Perspective: Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Image Credit: MattL_Images / Shutterstock

Background

Although the five-year survival rate in cases of localized prostate cancer is very promising (greater than 99%), metastasis or the prostate cancer progressing to the castration-resistant form of prostate cancer reduces the five-year survival rate to between 30% and 40%. Furthermore, while treatment options such as radiotherapy, chemotherapy, immunotherapy, and second-generation androgen receptor-signaling inhibitors can be used to treat advanced prostate cancer, these therapies only increase the survival rate by two to three years. Understanding the underlying mechanisms of prostate cancer can help improve and initiate early treatment.

Recent research has found that a pathway of regulated cell death, called ferroptosis, plays a significant role in the development of prostate cancer. Ferroptosis differs from the other forms of cell death, such as autophagy, apoptosis, and necrosis, in that it is iron-dependent and is driven by lipid peroxide build-up. Studies have found that the suppression of ferroptosis is linked to tumor pathogenesis, especially in prostate cancer.

Ferroptosis

Ferroptosis does not have the typical characteristics of apoptosis, such as the condensation of chromatin, apoptotic body formation, and cytoskeletal breakdown. Neither does it show the hallmarks of necrosis and autophagy, such as the swelling of organelles and the formation of the autophagosomes, respectively.

During ferroptosis, the mitochondrial size and cristae of the cells reduce, and the membrane density increases. Additionally, the polyunsaturated fatty acids that are part of the phospholipid membrane form peroxides. The lipid peroxidation could be initiated due to oxidation from iron overload, the mitochondria, or the production of reactive oxygen species due to iron. The lipid peroxidation process results in widespread damage and oxidative injury, leading to cell death.

Cells contain various intrinsic systems to circumvent lipid peroxidation and ferroptosis. The classical method involves the use of glutathione and glutathione peroxidase 4 to decrease the levels of lipid hydroperoxides, preserving the integrity of the phospholipid bilayer and preventing ferroptosis. Inhibition of ferroptosis can also occur through ferroptosis suppressor protein 1 or dihydroorotate dehydrogenase.

Ferroptosis and cancer

Given the association between ferroptosis and polyunsaturated fatty acids, cancer cells, which undergo substantial metabolic reprogramming and produce reactive oxygen species, are especially susceptible to ferroptosis. Cells in malignant tumors have higher energy and iron demands, which increases their susceptibility to ferroptosis. Prostate cancer cells depend on lipid metabolism for their high energy requirements, which causes the fatty acid metabolism in prostate cancer cells to be dysregulated.

Furthermore, factors such as lipid metabolism gene upregulation, rewiring of the oxidative phosphorylation metabolism, and increased tricarboxylic acid flux have been observed in both early and late-stage prostate cancer cells. These processes could increase the intracellular reactive oxygen species burden, promote lipid peroxidation, and cause perturbations in iron homeostasis.

The review discussed various mechanisms through which the susceptibility of cancer cells to ferroptosis could be exploited as potential treatment avenues for advanced cancers. Targeting the defense mechanisms that inhibit ferroptosis is a promising approach. Studies have suggested that targeting the glutathione peroxidase 4 inhibition mechanism could induce ferroptosis in cancer cells that do not respond to other treatment options.

Research also indicated that dihydroorotate dehydrogenase was not the primary ferroptosis inhibitor in cancer cells, and therefore, targeting dihydroorotate dehydrogenase might not be as effective as deletion of ferroptosis suppressor protein 1.

Furthermore, these studies highlighted the need to thoroughly understand the pitfalls and benefits of the various mechanisms to induce ferroptosis. Knockout studies in murine models revealed that glutathione peroxidase 4 was essential in various other processes and required for survival, while knocking out ferroptosis suppressor protein 1 resulted in no developmental changes, suggesting the latter to be a preferable method to induce ferroptosis.

This comprehensive review provided a detailed discussion of the various metabolic processes that could be exploited to make cancer cells vulnerable to ferroptosis. These methods included modulating the balance between mono- and polyunsaturated fatty acids, de-novo lipogenesis, de-novo synthesis of polyunsaturated fatty acids, and β oxidation. The researchers also expanded on the role of iron, cystine, glutamate, and glutathione metabolism in ferroptosis.

Conclusions

To summarize, the review provided an in-depth view of the regulated cell death process of ferroptosis, the factors that make cancer cells susceptible to ferroptosis, and its importance in prostate cancer therapy. They discussed the pathways through which ferroptosis is suppressed in cancer cells and the metabolic mechanisms that must be targeted to induce ferroptosis in prostate cancer cells selectively.
Journal reference:

Anh, H., Dominic, A., Lujan, F. E., Senthilkumar, S., Bhattacharya, P. K., Frigo, D. E., & Subramani, E. (2024). Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Nature Reviews Urology. DOI: 10.1038/s41585024008699, https://www.nature.com/articles/s41585-024-00869-9
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April 18, 2024
Exploring the versatile roles of tissue macrophages beyond immune defense

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A recent study published in Science Immunology summarized the role of resident tissue macrophages (RTMs) in homeostasis and disease.

Study: Resident tissue macrophages: Key coordinators of tissue homeostasis beyond immunity. Image Credit: ART-ur/Shutterstock.com

Background

Macrophages are evolutionarily conserved phagocytes ubiquitously present in almost all organs and tissues. It is recognized that the umbrella term macrophage comprises highly heterogeneous cells with diverse functions and roles.

RTMs are stable, long-lived subpopulations in different organs and tissues and have been linked to innate immunity and the pathogenesis of chronic inflammatory diseases. However, RTMs have broader functions beyond immunity.

Recently, exploring RTM subsets to functional, developmental, and spatial levels has become feasible, helping identify mechanisms of tissue homeostasis.

Notwithstanding these advances, substantial knowledge gaps remain. In the present review, researchers provided insights into conditions impacting RTM identity, division of labor among RTM subsets, and RTM dysfunction in disease.

Tissue microenvironment impacts RTM development

RTMs originate from embryonic progenitors or hematopoietic stem cell (HSC)-derived monocytes. The local microenvironment influences the trajectories of RTM differentiation upon seeding a tissue. In homeostasis, the local environmental cues shape RTM cell identity in a tissue-specific manner.

Further, the phenotypic and functional convergence of HSC-derived monocytes towards a tissue-specific RTM program is driven by the local environment.

However, inflammation or disease markedly impacts their differentiation. During such disturbance, the differentiation of HSC-derived monocytes skews toward pro-reparative, tumor-supportive, or pro-inflammatory phenotypes, differing from that of steady-state RTMs.

These inflammation-associated macrophages (iMacs) are short-lived, and upon resolution (of the disturbance), the tissue transitions to a distinct state, i.e., inflammation aftermath.

There may be permanent changes in the original homeostatic distribution and the composition of environmental factors. This was demonstrated in white adipose tissue, where HSC-derived RTMs acquired a more inflammatory phenotype following the resolution of chronic inflammation.

This post-inflammation scar led to HSC-derived RTMs being unable to differentiate into their original cellular state.

Coexistence of RTM subsets within tissues

Historically, it has been believed that organs and tissues are populated by unique tissue-specific RTMs during homeostasis, such as Langerhans cells in the skin, alveolar macrophages (AMs) in the lungs, Kupffer cells in the liver, and microglia in the brain.

However, a seminal work from 2010 showed that embryonic yolk sac progenitors, not monocytes, give rise to microglia.

This was also instrumental in revealing the embryonic origin of other RTMs. Studies have demonstrated that two distinct conserved RTM subsets populate most tissues in the interstitial space.

The authors term these RTM subsets as perivascular macrophages (PVMs). The PVMs precede with the name of the organ/tissue of residence.

Of the conserved PVM subsets, T cell immunoglobulin and mucin domain containing 4 (TIM4⁺) PVMs emerge during embryogenesis in multiple organs and are characterized by low levels of major histocompatibility complex II (MHCII) and high levels of TIM4, folate receptor beta (FOLR2), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and cluster of differentiation 206 (CD206).

By contrast, MHCII⁺ PVMs emerge from HSC-derived monocytes and are characterized by low/intermediate levels of FOLR2 and LYVE1 and high levels of CD206 and MHCII.

While some studies have observed a C-C motif chemokine receptor 2 (CCR2⁺) PVM subset, they are likely to be recent organ immigrants. Although some organs have unique tissue-specific subsets of RTMs, almost all organs share these two conserved PVMs.

Division of labor among RTMs

Microglia are the only brain RTM subset in contact with neurons. Several fundamental microglial functions beyond immunity have been uncovered more recently. Animal studies have shown that microglia are essential in neuronal development and fitness.

Microglia secrete growth factors critical for synapse formation. Additionally, they survey the brain microenvironment and modulate neuronal activity through synaptic engulfment and pruning.

Recent studies have revealed the presence of PVMs in perivascular spaces of the central nervous system (CNS). Further, these PVMs regulate cerebrospinal fluid (CSF) dynamics, and TIM4⁺ PVMs in the brain facilitate proper extracellular matrix (ECM) dynamics.

This idea was corroborated by the findings of abnormal ECM deposition and deterioration of CSF flow dynamics in aged mice, which are linked to a smaller ratio of brain TIM4⁺-to-MHCII⁺ PVMs.

The distinct locations of lung PVMs indicate they have specialized roles. For instance, lung MHCII⁺ PVMs may regulate neuronal interaction with stromal cells, whereas lung TIM4⁺ PVMs contribute to lung homeostasis.

Besides, lung TIM4⁺ PVMs may be involved in wound healing, while the MHCII⁺ counterparts may be involved in antigen presentation and immune activation.

Heart MHCII⁺ and TIM4⁺ PVMs produce growth factors to support proper cellular functions and adjust to physiologic demands. Cardiac PVMs are in close contact with cardiomyocytes and participate in mutual electric conduction, supporting normal cardiac contractions.

Gut muscularis MHCII⁺ and TIM4⁺ PVMs are close to blood vessels, myenteric plexus, and submucosal plexus. Gut MHCII⁺ PVMs are closely associated with neuronal bodies of the enteric nervous system.

Mechanistically, gut muscularis PVMs secrete bone morphogenetic protein 2 (BMP2) to regulate enteric neurons expressing the BMP2 receptor. Besides, they regulate gastrointestinal motility independent of the enteric nervous system. Recent studies suggest that gut PVMs promote neuroprotection and limit neuronal cell death.

RTM dysregulation and disease

It is established that HSC-derived iMacs are linked to chronic inflammatory diseases. This chronicity is thought to be due to ongoing inflammation leading to tissue function loss.

Nevertheless, how dysfunction or deviation of RTMs’ core homeostatic functions cause disease remains less studied. Usually, deviation is required for proper tissue repair.

However, it is not clear how long-term and persistent deviation affects tissue physiology and disease severity. Pulmonary alveolar proteinosis is caused by AM dysfunction, characterized by protein and surfactant accumulation in the lung alveolar space, limiting proper gas exchange and increasing susceptibility to infections.

This can occur due to mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF), autoantibodies against GM-CSF, or silica inhalation. Further, the absence or dysfunction of lung TIM4⁺ PVMs can result in increased fibrosis and loss of tissue function.

Likewise, dysregulation of heart TIM4⁺ PVMs exacerbates fibrosis following cardiac infarction. Loss of RTM’s core homeostatic functions may impact cancer development.

A recent study on breast cancer patients showed that those harboring tumors with increased breast TIM4⁺ PVMs had improved survival rates and T cell priming against the tumor.

This suggested that enhancing the TIM4⁺ PVMs’ homeostatic functions while inhibiting the activity of HSC-derived tumor-related macrophages can be effective for treatment.

Further, disruption of ECM remodeling in brain PVMs is associated with aging and Alzheimer’s disease (AD).

Concluding remarks

Taken together, ontogeny and local environmental cues shape the phenotype and heterogeneity of RTMs.

There is a strong division of labor among RTM subpopulations. The study proposed a unifying nomenclature for the two conserved RTM subpopulations and explored the roles of several unique tissue-specific RTM subsets in homeostasis and disease.

Nevertheless, further studies are required to delineate how RTM dysfunction leads to chronic inflammatory diseases fully.

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April 17, 2024
Vaccines targeting chronic diseases show promise in combatting age-related conditions

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In a recent review published in Nature Aging, researchers explored vaccine-based therapeutics for age-related disorders.

Study: Targeting aging and age-related diseases with vaccines. Image Credit: Ground Picture/Shutterstock.com

Background

Aging is a primary risk factor for chronic illnesses, marked by reduced physiological capabilities. Cell senescence, genomic instability, stem cell fatigue, and mitochondrial failure are characteristics.

Aging also increases the risk of chronic illnesses such as Alzheimer’s disease, atherosclerosis, osteoarthritis, type 2 diabetes, chronic obstructive pulmonary disease (COPD), and cancer. Healthy habits like calorie control and regular physical exercise help prevent age-related disorders.

However, small-molecule therapies have limits, and vaccines provide a potential technique to target specific antigens to generate immune responses.

About the review

In the present review, researchers present new developments in vaccines using senescent cells to target the etiological agents of aging and related diseases.

Immunology of senolytic vaccines that target aging

Vaccines stimulate the innate immunological system, making it rapidly respond to infection. This reaction activates adaptive immune cells, causing humoral antibodies to manufacture antibodies and cell-mediated immunity to attack infected cells. Vaccinations lead to pathogen-targeted memory cell development to accelerate response to reinfections.
Vaccines targeting microbes, cell populations, or chemicals can prevent and treat disease development. Senolytic vaccines, which target senescent cells, have been demonstrated to reduce arterial plaque development.

These vaccination techniques provide new pathways for managing age-associated disorders, with advantages such as fewer injections, increased patient adherence, cost-effectiveness, and improved targeting efficiency.

Senolytic vaccinations target senescent cells by targeting chemicals on their surfaces, using peptide-based platforms to eradicate them through complement-dependent cytotoxicity (CDC) or natural killer (NK) cell-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC).

Membrane proteins overexpressed in senescent cells are used as vaccine antigens or immune cell targets to stimulate the development of specific antibodies.

Tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) trigger a cluster of differentiation 4-expressing helper T cells, CD8+ cytotoxic T cells, and B cells to kill cancer cells.

Cancer vaccines use cell-based, virus-based, peptide-based, and nucleic acid-based platforms to stimulate adaptive immunity.

Research on vaccine-based strategies for age-related disorders

Alzheimer’s disease (AD) vaccinations attempt to lower the brain’s amyloid-beta (Aβ) and tau protein levels by stimulating the adaptive immune system to produce antibodies. Peptides with neuroprotective properties are potentially possible therapies.

Vaccines like ACI-24, UB-311, AV-1959D, ABvac40, ACI-35, AADvac1, and GV1001 target Aβ and tau proteins in innate immune cells. ACI-24 targets Aβ1-15 liposomes, UB-311 targets Aβ protein, AV-1959D targets deoxyribonucleic acid (DNA), ABvac40 targets Aβ protein, ACI-35 targets tau protein accumulation, and AADvac1 and GV1001 demonstrate long-term safety, tolerance, and immunogenicity.

Type 2 diabetes vaccinations target molecules like dipeptidyl-peptidase 4 (DPP4) and interleukin-1 beta (IL-1β) to restore levels and prevent problems.

The vaccines use peptide sequences to produce anti-DPP4 antibodies, increase glucose tolerance, restore beta cell mass, and reduce IL-1β production. They also couple prorenin epitopes with keyhole limpet hemocyanin (KLH), improving retinal blood circulation, decreasing microglia activation, and reducing gliosis and vascular leakage in diabetic rats.

Vaccines for age-related vascular diseases such as hypertension, abdominal aortic aneurysm (AAA), and atherosclerosis target molecules that regulate blood pressure, cholesterol, and blood vessel function. PMD-2850, PMD-3117, CYT006-AngQb, AT1R, ATRQβ-001, and ADR-004 inhibit angiopoietin 1 (Ang I) and age-related accumulation in hypertensive rats.

Vaccines containing KLH and Ang II decreased macrophage aggregation in the AAA wall, suppressed tumor necrosis factor (TNF) expression, and protected against elastic fiber injury.

The nerve growth factor (NGF) protein is an osteoarthritis target. Researchers covalently linked recombinant NGF proteins to virus-like particles (VLPs) derived from a cucumber mosaic virus with tetanus toxoid epitopes.

Vaccinated mice developed measurable antibodies against NGF and showed reversed pain behavior. ADAM metallopeptidase domain 12 (ADAM12) and GLI family zinc finger 1 (GLI1) levels are associated with fibrosis. Lentiviral vectors that encode these proteins decrease fibrotic activity in mice.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) can treat fibrosis. PCSK9Qβ-003, an epitope peptide, enhanced kidney fibrosis, and increased fatty acid beta-oxidation-associated variables among Ldlr+/− murine animals. The vaccine can treat kidney fibrosis, hypercholesterolemia, and atherosclerosis.

Conclusions

Based on the review findings, senescent cells play a significant role in age-related chronic disorders and demonstrate immunogenicity, making them candidates for targeted vaccine elimination.

However, vaccinations can cause adverse effects such as injection site redness, discomfort, fever, and headaches. Continuous evaluation of vaccination safety is required to comprehend long-term adverse effects.

Vaccines targeting key mediators in age-related disorders have seldom proven efficacy in slowing disease development. Researchers must select antigens from key disease drivers or investigate epitopes generating robust immune responses to boost vaccination effectiveness.

Combinatorial therapy incorporating vaccinations and immunomodulatory medications may be more effective.

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April 17, 2024
Research unveils bispecific antibodies for B-cell lymphoma treatment

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A new research paper was published in Oncotarget’s Volume 15 on April 12, 2024, entitled, “Novel therapeutic bispecific antibodies for B-cell lymphoma targeting IgM and other antigens on the B-cell surface.”

The B-cell receptor regulates B-cell proliferation and apoptosis. Aberrations in BCR signaling are associated with the development and progression of B-cell malignancies, such as mantle cell lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, many of which express the IgM type of BCR on their cellular surface.

Therefore, IgM is an attractive target for therapeutic antibodies against B-cell malignancies. However, soluble IgM competitively binds to anti-IgM antibodies in the serum, and these antibodies show insufficient cytotoxic activity. Thus, antibody therapy targeting IgM is hindered by the presence of soluble IgM in the blood. In this new study, researchers Takahiro Ohashi, Sayuri Terada, Shinsuke Hiramoto, Yuko Nagata, Hirokazu Suzuki, Hitoshi Miyashita, Tetsuo Sasaki, Yasukatsu Tsukada, and Keiko Fukushima from ZENOAQ (Zenyaku Kogyo Co., Ltd.) used a bispecific antibody to address this problem.

“In this study, we aimed to produce IgM-dependent bispecific antibodies targeting IgM and the other B-cell antigens such as CD20, CD32b (FcγRIIB), CD79b, and human leukocyte antigen (HLA)-DR using the Cys1m technology [10, 43–45]. Additionally, the correct IgG-like bispecific antibody structures were confirmed and their efficacies in the presence of soluble IgM were analyzed.”

The researchers generated bispecific antibodies bound to IgM and other B-cell antigens such as CD20 and HLA-DR using their own bispecific antibody-producing technology, Cys1m. These bispecific antibodies directly inhibited cell proliferation via cell-cycle arrest and apoptosis in vitro, although large amounts of soluble IgM were present. Additionally, a bispecific antibody bound to IgM and HLA-DR (BTA106) depleted B-cells in cynomolgus monkeys.

“These data suggest that anti-IgM/B-cell surface antigen-binding specific antibodies are promising therapeutic agents for B-cell malignancies. Moreover, the bispecific antibody modality can potentially overcome problems caused by soluble antigens.”

Source:

Journal reference:

Ohashi, T., et al. (2024). Novel therapeutic bispecific antibodies for B-cell lymphoma targeting IgM and other antigens on the B-cell surface. Oncotarget. doi.org/10.18632/oncotarget.28578.

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April 16, 2024
Study reveals human gut plasmid with biomarker potential

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A component of the human intestinal flora that has been little studied to date is the focus of a new study. Plasmids are small extrachromosomal genetic elements that frequently occur in bacterial cells and can influence microbial lifestyles – yet their diversity in natural habitats is poorly understood. An international team led by Prof. Dr. A. Murat Eren from the Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB) reports in the science journal Cell, a mysterious plasmid, is one of the most numerous genetic elements in the human gut that could potentially serve as a powerful biomarker for identifying health hazards such as fecal contamination of water or human disorders such as Inflammatory Bowel Disease. According to the team’s analyses, this plasmid is present in the intestines of more than 90 percent of individuals in industrialized countries.

Plasmids are extrachromosomal DNA sequences which are common to cells from all domains of life. Eren describes them as “typically small genetic entities that carry additional genes”. They can be exchanged between different bacterial cells and even between different types of bacteria. The replication of plasmids is dependent on their host cells: but they make up for it by providing their hosts with in some cases extremely important fitness determinants. For instance, some plasmids contain genes that encode antibiotic resistance, which help their bacterial hosts to survive antibiotics, contributing one of the most pressing public health concerns around the globe.

There are also other plasmids which, according to the research to date, do not contain genes encoding obvious beneficial functions for their host. “These so-called ‘cryptic plasmids’ are often referred to as genetic parasites. They remain a mystery in microbial ecology because from an evolutionary perspective they should not exist at all,” explains Eren, a computer scientist and Professor of Ecosystem Data Science at the University of Oldenburg.

Identifying plasmids has been a difficult undertaking so far. For some time now, scientists have been able to extract genetic material directly from environmental samples and, for example, analyze the microbial community in the human gut in its entirety, without having to cultivate individual bacterial organisms. However, the ability to confidently distinguish what is a plasmid among this conglomeration of genetic material, referred to as the metagenome, poses a considerable challenge.

To solve this problem, Eren and his colleagues developed a new machine learning approach. As the team reported in an article recently published in the science journal Nature Microbiology, using this approach they identified over 68,000 plasmids in human intestinal flora, and also discovered that a certain cryptic plasmid called pBI143 was particularly abundant in their dataset.

One of the most numerous genetic entities in the human gut

In the study published in Cell, the team of researchers took a closer look at this plasmid, which consists of only two genes that rather surprisingly only serves for its own replication and mobilization across bacterial cells with no other clear benefit. To better understand the ecology of pBI143, the team analyzed 60,000 human and 40,000 environmental metagenomes generated from various habitats.

“We found that pBI143 has a list of very interesting features,” Eren explains. The team discovered that more than 90 percent of people in industrialized countries carry the plasmid and that on average it is one of the most numerous genetic entities in the human gut. “On average it was more than ten times as numerous as a viral genome which was previously thought to be the most abundant genetic extrachromosomal element in the human gut,” says the researcher.

Further analyses revealed that the plasmid occurred almost exclusively in the human gut but was virtually absent in datasets from other environments such as the oceans, soils, plants and the digestive organs of animals and their feces. The only other samples in which the researchers were able to detect the characteristic gene sequence for these plasmids was in samples from environments that are influenced by humans, such as waste water, hospital surfaces and laboratory rats.

Due to its sheer numbers, prevalence across humans, and its conservancy across human populations, the team of researchers hypothesized that pBI143 could, for instance, be used as a biomarker in testing for fecal contamination.

In fact, we were able to show that this plasmid is a more sensitive marker for detecting fecal contamination in drinking water compared to state-of-the-art biomarkers based on specific gene sequences of human intestinal bacteria.”

Dr. A. Murat Eren, Professor of Ecosystem Data Science at the University of Oldenburg

Non-invasive method to quantify progress of IBD

The team also identified another potential application of this prevalent genetic entity in the context of human disorders such as Inflammatory Bowel Disease (IBD), a medical condition that affects 3 million people in Europe alone. They were able to demonstrate that the relative copy number of this cryptic plasmid increased almost four times in the intestines of people suffering from IBD compared as in the intestines of healthy individuals, suggesting that the changes of the copy number of the plasmid can serve as a non-invasive method to quantify the disease progress or severity.

At the HIFMB, Eren’s team is developing new tools at the intersection of computer science and microbiology to identify and characterize naturally occurring plasmids and other mobile genetic elements in bacteria that live in the ocean. They strive to gain a better understanding of the ecology and evolution of microbes, and strategies that enable to them to respond to their everchanging environments for new biotechnological applications that can ameliorate crises we face.

Source:

Journal reference:

Fogarty, E. C., et al. (2024). A cryptic plasmid is among the most numerous genetic elements in the human gut. Cell. doi.org/10.1016/j.cell.2024.01.039.

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April 16, 2024
Study shows potential for universal flu vaccine with broad antibody response
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A recent study published in the journal Nature Communications observed antibody breadth and effector functions as important immune correlates that can be used to develop universal influenza vaccines. This vaccine could be effective against all influenza virus strains, even those having pandemic potential.

Study: Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children. Image Credit: Africa Studio / Shutterstock

Background

Children are particularly vulnerable to influenza viruses that cause seasonal epidemics and sporadic pandemics. Seasonal influenza epidemics not only lead to an upsurge in hospital admissions but also increase mortality rates in older adults with comorbidities. Many studies have shown that seasonal influenza vaccines provide limited protection against influenza viruses that have the potential to cause a pandemic. However, the 2009 H1N1 pandemic (pH1N1) revealed the effectiveness of seasonal vaccines in protecting children and older adults from the infection. This protection could be due to cross-reactive antibody responses.

Compared to children, adults possess additional immune correlates, such as T-cell responses and non-neutralizing antibody functions. This is the reason why children require higher concentrations of HAI antibodies for an equivalent amount of immune protection from the infection. To design a next-generation vaccine, it is important to identify immune correlates of protection. In the context of pH1N1 infection, HA-stem-specific antibodies play a crucial role in providing protection, which is mediated by the Fc Receptor (FcR) function.

Some antibodies that can cross-react between pandemic, seasonal, and avian influenza viruses could reduce the severity of influenza virus infection. In this context, serum antibodies, particularly IgG, can facilitate effector functions, such as directing immune cells to kill infected cells, engulfing infected cells via antibody-dependent phagocytosis (ADCP), and promoting antibody-dependent cellular cytotoxicity (ADCC). These functions are mediated by Fc gamma receptors (FcγR) 3a and FcγR2a.

Mechanistically, FcγR 3a and FcγR2a employ macrophages and natural killer (NK) cells to remove viruses-infected cells. Cross-reaction of ADCC antibodies has been associated with targeting conserved antigenic sites of influenza virus hemagglutinin (HA), the Nucleoprotein (NP), and Matrix 1 (M1).

About the Study

The current study identified several gaps in research regarding antibody effector functions. For instance, few studies have assessed the vaccine-induced ADCC changes, longitudinal durability of vaccine-induced antibody FcR binding and isotype changes, and the alterations in HA-specific antibody responses with vaccination and infection. The currently performed randomized placebo control trial (RCT) investigated the influenza-specific antibody breadth and function of seasonal (S1) H1N1 vaccination and pH1N1 infection.

The antibody features, particularly HAI titer, from seasonal vaccination that could have helped in reducing or delaying contraction of pH1N1 were assessed using selected archived samples. These samples were collected from NCT00792051, a randomized placebo-controlled trial and its follow-up study that used school children between 6 and 17 years old.

A subset of children who received any influenza vaccination in Year 1 (V1) or not (placebo-V0) was selected for secondary analyses, which helped determine the effectiveness of vaccination against pH1N1 infection.

Study Findings

The current study indicated that non-neutralizing antibodies are highly cross-reactive between different influenza strains and subtypes, which could play an important role in reducing the incidence and severity of infection.

Detecting antibody functions other than HAI is vital to developing next-generation vaccines. This study identified the serological correlates that play an important role in protecting children from pandemic infection. In 2009, when schools were closed for two months, H1N1 transmission was low. However, soon after schools reopened in September 2009, more than 50% of the students were infected within a few months. A very low community uptake of the monovalent pH1N1 vaccine has been documented.

The half-life of different antibody subclasses alters significantly. The current study observed that seasonal vaccination enhances Fc effector functions of pH1N1 specific NP, HA, and neuraminidase (NA) antibodies. However, their function was short-term as it waned off within one year of vaccination. A greater antibody decline was observed in unvaccinated children.

Seasonal vaccination did not boost FcR effector functions to other seasonal-specific antibody responses. Unvaccinated, uninfected children also exhibited increased FcR-mediated effector functions of pandemic-specific NA, HA, and NP antibodies. These children displayed a higher antibody level of NK cell function. pH1 antibodies against H3-HA responses were associated with cross-reactive avian H5-specific IgG, FcγR2a, and FcγR3a responses. This finding implies that cross-reactive responses are less focused and are not trained by seasonal virus exposure of other groups.

Considering the experimental results, vaccination and prior infection are not associated with the lack of infection in unvaccinated, uninfected children or susceptibility of V1S1 children. More research is required to understand the host factors leading to these outcomes.

Results also indicated that group 2 H3 HA-specific IgG3 antibodies are negative predictors of infection. However, seasonal H1 and pH1-IgG3 antibodies before infection were positively associated and, therefore, protected against infection.

Conclusions

This study shows how universal influenza vaccines, effective against seasonal to pandemic viruses, can be developed. Antibody breadth and FcR effector functions are two important immune correlates that could be exploited to develop this vaccine.
Journal reference:

Jia, J. Z. et al. (2024) Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children. Nature Communications. 15(1), 1-15. DOI: 10.1038/s41467-024-47590-0, https://www.nature.com/articles/s41467-024-47590-0
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April 16, 2024
Ketamine’s rapid impact on depression linked to immune system pathways
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In a recent study published in Molecular Psychiatry, researchers review the anti-inflammatory effects of ketamine in the peripheral and central nervous systems. To this end, all relevant articles were obtained from PubMed and Web of Science databases, with both animal and human studies published until September 2023 considered for the analysis.

Study: Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: Can the complement system complement ketamine’s antidepressant effects? Image Credit: Jack_the_sparrow / Shutterstock.com

Treating major depressive disorder

Major depressive disorder (MDD) is a mood disorder associated with persistent feelings of loss of interest and sadness. Current estimates indicate that over 300 million individuals are affected by MDD globally, about 700,000 of whom commit suicide each year. Altered neurotrophin levels and monoamine dysregulation are both mechanisms that have been attributed to manifestations of MDD.

Monoamines associated with noradrenergic, serotoninergic, and dopaminergic activities can be regulated through certain pharmaceutical agents to improve the cognition, sleep, and mood of MDD patients. However, conventional monoamine antidepressant therapy has only been shown to be effective in 30-40% of patients with MDD.

According to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a significant number of MDD patients do not respond to standard treatment. Patients who fail to respond to two antidepressants of suitable dosage are known to suffer treatment-resistant depression (TRD).

Racemic (R, S)-ketamine, which is more commonly referred to as ketamine, and (S)-ketamine (esketamine) have shown significant positive effects on MDD. As compared to conventional treatments, ketamine has been shown to exert antidepressant effects within a few hours. Many TRD patients have also responded positively to a single ketamine infusion.

Mechanism of action of ketamine for MDD treatment

The mechanisms that underlie the antidepressant effects of ketamine are associated with the N-methyl-D-aspartate (NMDA) receptor, opioid pathway, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and mechanistic target of rapamycin (mTOR).

Various neuronal cells, including microglia and astrocytes, regulate neuroinflammation. Individuals with MDD often exhibit lower levels of glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). In these patients, an acute administration of ketamine normalized these levels, thus improving their mood.

In vivo experimental findings have also shown that ketamine has an inhibitory effect in lipopolysaccharide (LPS)-induced microglial activation, which led to improvements in depressive-like behaviors. Rodent studies have also reported that transforming growth factor β (TGF)-β, an anti-inflammatory molecule inhibiting excessive microglial activation, is associated with the differential antidepressant effects of ketamine enantiomers.

Mouse models have revealed that (R)-ketamine, and not (S)-ketamine, alleviates stress-induced reduction in the expression of Tgfb1 and its receptors Tgfbr1 and Tgfbr2. Nevertheless, additional research is needed to clarify the microglia-based mechanisms underlying the antidepressant effects of ketamine.

Patients with MDD exhibit higher interleukin 6 (IL-6) and tumor necrosis factor ⍺ (TNF-⍺) levels than non-depressed individuals. One rodent study revealed ketamine administration normalized these levels and improved MDD symptoms.

Higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) have been observed in patients with MDD. Administration of 0.5 mg/kg ketamine infusions for twelve days led to symptomatic improvement that was associated with significant downregulation of GM-CSF.

Ketamine and the immune response

The antidepressant effects of ketamine have been linked with the complement system, which is a vital component of synaptic plasticity. The complement system comprises 30 proteins that are involved in the classical, alternate, and lectin pathways, all of which converge in C3 cleavage, a major complement component.

Complement proteins play a crucial role in the regulation of cell proliferation, maturation, and responsiveness. Activation of the complement system results in the release of complement and immune molecules that are linked with inflammatory responses.

Increased levels of serum complement components C3a and C5a have been observed in bipolar disorder. Similarly, a high concentration of serum C1q levels is found in patients with MDD.

An in vivo experiment with C5a receptor knockout mice highlighted the neuroprotective role of C5a against glutamate excitotoxicity-induced apoptosis through elevated expression and regulation of glutamate receptor subunit 2 (GluR2). Glutamatergic modulation has been established as a mechanistic commonality between the complement system and ketamine.

Ketamine also activates mTORC1 by triggering the brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and NMDA receptors. Additionally, the the C3a ligand-C3a receptor in CD4 + T-cells leads to mTOR activatiwhich is on, essential for cell survival. Complement-mTOR activation also modulates many stress and metabolic pathways, such as cytokine secretion, oxidative phosphorylation, and inflammasome activation.

Conclusions

The current study indicated the potential association between the complement system and the antidepressant effects of ketamine. Nevertheless, additional studies are needed to improve treatment outcomes for MDD using ketamine.
Journal reference:

Quintanilla, B., Zarate, C. A., and Pillai, A. (2024) Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: Can the complement system complement ketamine’s antidepressant effects? Molecular Psychiatry; 1-10. doi:10.1038/s41380-024-02507-7
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April 16, 2024
Researchers identify a novel mechanism connected to the early stages of Alzheimer’s disease

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Alzheimer’s disease (AD) remains one of the most challenging and prevalent neurodegenerative disorders, affecting millions of individuals worldwide. In a new study published in Developmental Cell, researchers from the lab of Wim Annaert (VIB-KU Leuven) have identified a novel mechanism potentially connected to the early stages of AD. They demonstrated that a fragment of the amyloid precursor protein (APP), called APP-CTF, disrupts communication between cellular compartments crucial for calcium storage and waste disposal, which could be an early event preceding neuronal cell death. These findings, with potential implications for the development of new AD treatments, suggest that preventing APP-CTF accumulation needs to be taken into account to develop more effective treatments.

Alzheimer’s disease is characterized by the progressive loss of cognitive function, memory impairment, and behavioral changes. One of the visible features in the brains of people with Alzheimer’s disease is the formation of amyloid plaques – clumps of β-amyloid (Aβ) peptides, which are degraded products of amyloid precursor protein (APP). These Aβ-fragments accumulate in neurons early in the disease, even before cognitive decline is observed.

New research, however, suggests that there might even be earlier events happening in the AD brain before plaque formation and that the APP protein plays a role in these early stages. The mechanism behind this remained a mystery until now.

In their latest study, the lab of Wim Annaert at the VIB-KU Leuven Center for Brain & Disease Research identified a mechanism explaining how APP may contribute to these early stages of AD. This discovery could lead to a new direction in AD research and treatment approaches.

Disrupting cellular communication

APP is found in the cell membranes of brain cells. The brain constantly produces new APP molecules while breaking down and removing old ones. This process involves enzymatic scissors, with gamma-secretase being the final one that generates the well-known and well-studied Aβ peptides in AD.

For a long time, it was thought that blocking gamma-secretase would be the logical step to prevent the production of toxic Aβ fragments. However, this leads to the accumulation of their precursor, the APP-C-Terminal Fragments, or APP-CTFs. Now, the researchers have discovered that these fragments are also toxic to neurons. They appear to accumulate between the endoplasmic reticulum (ER), the compartment that is crucial for lipid synthesis and calcium storage, and the lysosomes, the so-called ‘waste bins’ of neurons, which are critical for degrading the cell’s waste products.

“By doing so, APP-CTFs disrupt the delicate balance of calcium within lysosomes,” explains Dr. Marine Bretou, first author of the study. “This disruption triggers a cascade of events. The ER can no longer effectively refill lysosomes with calcium, leading to a buildup of cholesterol and a decline in their ability to break down cellular waste. This results in the collapse of the entire endolysosomal system, a crucial pathway for maintaining healthy neurons.”

The new study further supports that the APP-CTFs resulting from suppressing gamma-secretase might actually be the culprit behind endolysosomal dysfunction, as observed in the very early stages of AD.

A paradigm shift in understanding the early stages of AD pathogenesis

This research significantly advances our comprehension of the potential causes of disease in the early stages of AD. A remarkable outcome of this study is that these early stages could be caused by another fragment of the same APP molecule rather than Aβ. This has significant implications for the current therapeutic approaches that aim to clear the AD brain from amyloid plaques, as they tend to ignore the toxic effects of other fragments. Other attempts focus on tau proteins or neuroinflammation, which are other hallmarks of AD progression that target later events. However, early intervention is likely the key to stopping or even preventing AD.

“The failure of clinical trials using gamma-secretase inhibitors may be explained by the fact that we were focusing on only one culprit and at a too late stage in the disease,” explains Prof. Wim Annaert, lead author of the study. “Our research findings suggest that gamma-secretase modulators, which can help promote clearance of toxic APP-CTFs without blocking the enzyme completely, may be a more relevant target for early intervention in AD. The key might be finding the right balance between APP-CTF clearance and plaque prevention.”

Looking ahead, the scientists are joining efforts with colleagues to develop these modulators based on these novel insights and will continue exploring cellular homeostasis in the early stages of AD.

Source:

Vlaams Instituut voor Biotechnologie

Journal reference:

Bretou, M., et al. (2024) Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-ER contact sites. Developmental Cell. doi.org/10.1016/j.devcel.2024.03.030.

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April 15, 2024