Carbon Chemist

Tag: Tumor

  • Biomechanical model simulates breast tumor growth

    Biomechanical model simulates breast tumor growth

    [ad_1]

    Scientists from Universidad Carlos III de Madrid (UC3M) and Johns Hopkins University (JHU), in the USA, have analyzed the growth of breast tumors from a biomechanical perspective and have created a computational model that simulates the invasion process of cancer cells, depending on the characteristics of the surrounding tissue and cell junctions, among other parameters. This type of model will help predict the evolution of a tumor in patients from its mechanical properties (stiffness, density, etc.) of the surrounding microenvironment, which can be determined through a biopsy or imaging techniques.

    The growth process of a solid tumor involves its expansion through the surrounding tissue, usually composed of a fibrillar matrix (for example, collagen). Its expansion depends on many factors such as the total number of tumor cells, their volume and stiffness, their access to nutrients, and the mechanical properties of the tissue in which they are developing. Supported by experimental in vitro models, these UC3M and JHU researchers have developed a model that allows for simulating the evolution of the tumor growth on a computer, taking these factors into account.

    In this model we have simulated how breast tumor cells invade the surrounding tissue, and how they proliferate more or less depending on how stiff and porous the surrounding tissue is or how strong the cell junctions with other cells are.”


    Daniel García González, Associate Professor in UC3M’s Continuum Mechanics and Structural Analysis Department and head of the ERC 4D-BIOMAP project

    To do this, the researchers have worked with spheroids to simulate how cells behave in a real tumor under different mechanical conditions. These spheroids consist of groups of tumor cells embedded in a fibrillar matrix whose characteristics can be modulated. “They are very powerful systems that are increasingly being used to study tumor behavior and to study possible therapies”, explains another of the researchers, Arrate Muñoz-Barrutia, a Professor in UC3M’s Bioengineering Department.

    Thanks to these spheroids, researchers have been able to modify certain biological or mechanical aspects of these tumors in the laboratory and evaluate how these variables influence cell proliferation and migration. They then transformed these observations into mathematical equations implemented in a computational model. In this way, they were able to test in parallel (in the computer simulator and in the experimental model with the spheroids in the laboratory) the variables that influence the growth of these tumors. “Our new multi-compartment spheroid system allowed us to control and modulate the system’s biomechanical properties via collagen density and E-cadherin expression, which are known to play a role in breast cancer progression. It was very exciting to work with this team to see the story come together from both experimental and computational perspectives”, says another of the study’s authors, Denis Wirtz, from JHU’s Chemical and Biomolecular Engineering Department.

    “While experimentally, proliferation and invasion are often measured as two independent parameters, we observed a strong coupling of these processes. Although they could not be isolated using traditional experimental outputs, the computational model allowed us to study these processes independently and gather insights from the biomechanical properties of our system”, adds another of the JHU team’s researchers, Ashleigh Crawford.

    Future applications of this study are promising, according to the researchers. “If we know which mechanical parameters determine whether the tumor grows more or less, then we could use that data to improve treatment or develop new drugs in the medium or long term”, says Daniel García González. “We think that these studies open the door to the development of technologies that allow us to characterize the mechanics of the tumor, which can add relevant information for the choice of cancer therapy”, adds Arrate Muñoz-Barrutia.

    The team of scientists also highlights the importance of multidisciplinary research in this case, since contributions have been made from computational and mathematical to purely biological fields. “My training as a biomedical engineer, studying at UC3M, has allowed me to collaborate in all parts of this research and to create bridges of communication between disciplines that use different terminologies”, says another of the study’s authors, Clara Gómez Cruz, a PhD student in UC3M’s Continuum Mechanics and Structural Analysis Department.

    This research is part of 4D-BIOMAP (Biomechanical Stimulation based on 4D Printed Magneto-Active Polymer), a project funded by the European Research Council through an ERC Starting Grant from the European Union’s Framework Programme for Research and Innovation, Horizon 2020 (GA 947723). It has also received funding from the USA’s National Institute of Health and National Cancer Institute.

    Source:

    Universidad Carlos III de Madrid – Oficina de Información Científica

    Journal reference:

    Crawford, A. J., et al. (2024). Tumor proliferation and invasion are intrinsically coupled and unraveled through tunable spheroid and physics-based models. Acta Biomaterialia. doi.org/10.1016/j.actbio.2023.12.043.

    [ad_2]

    Source link

  • Concomitant pharmacotherapy overcomes immunotherapy challenges in aggressive blood cancer

    Concomitant pharmacotherapy overcomes immunotherapy challenges in aggressive blood cancer

    [ad_1]

    Researchers at the University of Zurich and the University Hospital Zurich have discovered that a specific mutation in the cancer cells of an aggressive type of blood cancer can prevent novel immunotherapies such as CAR T-cell therapy from working. Their study also explains why the cancer cells are resistant and how this resistance can be overcome: through concomitant pharmacotherapy or genetically improved CAR T-cells.

    Acute myeloid leukemia (AML) is an aggressive form of blood cancer. It is caused by mutations in a large number of genes that are acquired in the course of a person’s life. One of these genes – the tumor suppressor gene TP53 – plays a key role. Normally, TP53 helps to prevent the development of tumors. Blood cancer patients in whom this gene is mutated, however, face an extremely poor prognosis, as their genes are resistant to conventional chemotherapeutic agents. Intensive research is therefore being carried out into new therapeutic approaches, such as CAR (chimeric antigen receptor) T-cells, which are already being used successfully for other cancers of the blood.

    Mutation in blood cancer cells weakens immunotherapy defense cells

    An international research team led by Professors Markus Manz and Steffen Boettcher from the University of Zurich (UZH) and the Department of Medical Oncology and Hematology at the University Hospital Zurich (USZ) has now shown that TP53-mutant AML cells are also significantly more resistant to a new type of immunotherapy – CAR T-cell therapy – than AML cells without the mutated gene.

    The reason for the poorer effect of CAR T-cells with mutated TP53 is that these immune cells are exhausted more quickly and are therefore less active against the cancer cells.”

    Steffen Boettcher, chief of service at USZ

    In CAR T-cell therapy, certain immune cells – the T-cells – are extracted from a patient’s blood. These immune cells are then genetically modified in the lab so that they form numerous new contact points (CARs) on their surface. Reintroduced into the patient, these CAR T-cells are able to recognize certain surface structures on the tumor cells, which enables the CAR T-cells to identify the cancer cells and destroy them in a targeted manner. Various CAR T-cell products are currently being tested against AML in early clinical trials.

    Concomitant pharmacotherapies or advanced CAR T-cells are effective against resistant cancer cells

    In their study, the researchers not only examined the mechanism underlying the resistance of mutated AML cells to CAR T-cell immunotherapy; they also found out how the endurance of CAR T-cells can be increased and a weak point of TP53-mutant AML cells can be exploited to overcome this resistance. Through additional pharmacological concomitant therapies or further genetic improvement of the CAR T-cells, they were able to drastically increase the effectiveness of CAR T-cells against TP53-mutant AML cells to the point where there was no longer any therapeutic difference compared to non-mutated AML cells.

    “This proof-of-principle study shows that concurrent pharmacological therapies and genetically engineered CAR T-cells are promising strategies to develop more effective and tolerable immunotherapies for patients with TP53-mutant AML,” says head of clinic Markus Manz.

    Source:

    Journal reference:

    Mueller, J., et al. (2024). Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells. EMBO Molecular Medicine. doi.org/10.1038/s44321-024-00024-2.

    [ad_2]

    Source link

  • Lactate’s role in driving cancer cachexia uncovered

    Lactate’s role in driving cancer cachexia uncovered

    [ad_1]

    A recent Nature Metabolism study reports that circulating lactate levels are positively associated with weight loss in cancer cachexia patients. Mouse model experiments also revealed that adipose-specific G-protein-coupled receptor 81 (GPR81) is a key mediator of the catabolic effects of lactate. 

    Study: Activation of GPR81 by lactate drives tumor-induced cachexia. Image Credit: Pixel-Shot / Shutterstock.com Study: Activation of GPR81 by lactate drives tumor-induced cachexia. Image Credit: Pixel-Shot / Shutterstock.com

    What is cachexia?

    Cachexia is a complicated metabolic syndrome that is associated with rapid body weight loss, including loss of fat and muscle mass.

    Patients with cancer cachexia often develop anemia, fatigue, asthenia, and anorexia, which deteriorate their quality of life and reduce their tolerance to cancer therapies. As a result, cachexia accounts for around 20% of patients with cancer-related deaths.

    To date, the precise mechanism responsible for the development of cancer cachexia is not well understood. Previous studies have shown that inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor (TNF), interferon γ (IFN-γ), and transforming growth factor-β, induce the remodeling of adipose and muscle due to accelerated growth of cancer cells, all of which contribute to the pathogenesis of cancer cachexia.

    Anti-inflammation treatments have not been associated with positive effects in alleviating cancer cachexia. Therefore, more research is needed to better understand the association between tumor manifestations and poor host metabolism.

    About the study

    The current study focuses on causally identifying the connecting factors between tumors and extensive catabolism in cancer cachexia. To determine serum lactate levels, samples collected from lung adenocarcinoma patients were used to calibrate the Biosen C-Line glucose lactate analyzer.

    The systemic metabolic changes associated with cachexia were profiled using a mouse xenograft model of Lewis lung cancer (LLC) cells. Mice with tumor burden exhibited significant weight loss with reduced white adipose tissue (WAT). 

    Study findings

    Metabolomics screening of a mouse model of cancer cachexia identified lactate as the top differential metabolite. The identity of this metabolite was corroborated by the peak in the mass spectrum, which was compared to the standard. 

    Lactate levels were strongly correlated with reduced body weight, particularly among patients with lung adenocarcinoma with cancer cachexia. Higher circulating and adipose interstitial lactate levels were observed before body weight loss. Additionally, the wasting phenotype lactate infusion results were similar to those induced by the tumor.

    An osmotic minipump-mediated lactate infusion led to a persistent average increase of circulating lactate without a change in blood pH; however, d-lactate exhibited did not appear to influence weight loss. The sustained high lactate levels in many cancer patients were negatively associated with their prognosis. 

    Adipose GPR81 was identified as the primary mediator of lactate’s pro-catabolic effects. More specifically, GPR81 deficiency was found to block lactate infusion- and tumor-triggered cachectic manifestations, thus establishing lactate/GPR81 as the key connection between metabolic reprogramming in cancer cachexia and tumors.

    The catabolic remodeling of WAT has also been identified as an early pathological event in cancer cachexia. In mouse models, depletion of key enzymes in lipolysis alleviated cachectic phenotypes, thereby confirming the crucial role of adipose tissue wasting in cancer cachexia.

    A lactate-stimulated cachectic pathway activated the GPR81-Gαi/o-Gβγ-RhoA/ROCK1-p38 signaling cascade, not accompanied by the upregulation of parathyroid hormone-related protein (PTHrP). To trigger WAT browning and lipolysis, chronic elevation of blood lactate is sufficient.

    Additionally, phosphoproteomics data showed the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the GPR81−/− iWAT. This activation of ERK1/2 in GPR81-deficient mice could influence persistent adipogenesis, thereby muting lactate- and tumor-induced adipose wasting. 

    Conclusions

    The current study identified host GPR81 as the key mediator of cancer cachexia, with lactate activating GPR81 to ultimately support tumor growth. This observation aligns with previous studies reporting the inhibition of GPR81 expression suppressing the growth of pancreatic and breast cancer cells. The experimental findings strongly suggest that the palliation of cachectic symptoms in GPR81−/− is mediated through GPR81 deficiency in the host.

    Both in vitro and in vivo experiments associated with tumor growth revealed that the lack of GPR81 expression in LLC cells repressed cancer proliferation. Thus, lactate/GPR81 contributes to both cancer progression and cachexia, which deteriorates disease outcomes.

    Mechanistically, lactate activates GPR81, which induces adipose metabolic remodeling through Gαi/o-Gβγ–RhoA/ROCK1–p38 signaling cascade. This leads to muscle dystrophy and systemic hypercatabolism.

    Taken together, the study findings indicate that GPR81 could be targeted and blocked to alleviate metabolic impairments involved in cancer cachexia.

    Journal reference:

    • Liu, X., Li, S., Cui, Q., et al. (2024) Activation of GPR81 by lactate drives tumor-induced cachexia. Nature Metabolism. doi:10.1038/s42255-024-01011-0

    [ad_2]

    Source link

  • Cryoablation could be a new treatment path for breast cancer patients with large tumors

    Cryoablation could be a new treatment path for breast cancer patients with large tumors

    [ad_1]

    A minimally invasive technique that uses ice to freeze and destroy small, cancerous tumors has now been proven effective for breast cancer patients with large tumors, providing a new treatment path for those who are not candidates for surgery, according to new research to be presented at the Society of Interventional Radiology Annual Scientific Meeting in Salt Lake City.

    For patients who have larger tumors but can’t undergo surgery, this approach could be more effective than the current standard of care for patients who are not surgical candidates. When treated with only radiation and hormonal therapy, tumors will eventually return. So, the fact that we saw only a 10% recurrence rate in our study is incredibly promising.”


    Yolanda Bryce, M.D., interventional radiologist at Memorial Sloan Kettering Cancer Center

    Cryoablation is a minimally invasive treatment that uses imaging guidance such as ultrasound or computed tomography (CT) scan to locate tumors. An interventional radiologist will then insert small, needle-like probes into the breast to create an ice ball that surrounds the tumor, killing the cancer cells. When combined with hormonal therapy and radiation, patients can have nearly 100% of their tumors destroyed. If the tumors do grow, patients can be treated with cryoablation multiple times to control growth. The treatment has been successfully used to treat tumors smaller than 1.5 cm, but its effectiveness on larger tumors was not extensively demonstrated until now.

    This retrospective study assessed outcomes for 60 patients who underwent cryoablation because they were not candidates for surgery or refused surgery after consultation with a breast surgeon due to age, cardiac issues, hypertension, or currently undergoing chemotherapy for another cancer. Their tumor sizes ranged from 0.3 – 9 cm with an average size of 2.5cm. Patients with tumors larger than 1.4 cm were treated with multiple probes (one probe placement for each centimeter of disease). In a follow-up after 16 months, the recurrence rate was just 10%.

    “Surgery is still the best option for tumor removal, but there are thousands of women who, for various reasons, cannot have surgery,” said Bryce. “We are optimistic that this can give more women hope on their treatment journeys.”

    The procedures were performed with local anesthesia or minimal sedation, depending on the eligibility and preference of the patient. The freeze-thaw cycle started with 5-10 minutes of freezing, followed by 5-8 minutes of passive thaw, and then 5-10 minutes freezing at 100% intensity. Patients were able to go home on the same day, following the treatment.

    The researchers will continue to follow the patient cohort to collect data on long-term effectiveness and to better understand the impact that adjuvant (e.g. hormone therapy and radiation) therapies combined with cryoablation can have on this patient population.

    [ad_2]

    Source link

  • Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

    Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

    [ad_1]

    Monitoring levels of DNA shed by tumors and circulating in the bloodstream could help doctors accurately assess how gastroesophageal cancers are responding to treatment, and potentially predict future prognosis, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

    The study tracked minimal residual disease (the amount of cancer left following treatment) by analyzing circulating tumor DNA (ctDNA), showing how these “liquid biopsies” can provide valuable insights into treatment outcomes over time. Absence of ctDNA was seen occurring together with specific activation of T cells that are part of the immune system’s defense to recognize and fight cancer. 

    “We found that the elimination of ctDNA was a good indicator of patients’ cancer-free survival,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., senior co-author of the study and associate professor of oncology and director of the thoracic oncology biorepository at Johns Hopkins.

    Anagnostou is also leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board and co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins. “We were gratified to see tumor shrinkage at a molecular level together with the immune system flaring up and clearing the tumor,” she says.

    The findings, reported in a paper published March 19 in Nature Medicine, emerged from a clinical trial examining the safety and efficacy of two immunotherapy drugs -; nivolumab and relatlimab -;as part of pre-operative treatment for patients with operable esophageal and gastroesophageal junction cancer.

    Patients with gastroesophageal cancer who have successfully completed the standard treatment of chemoradiotherapy followed by surgery unfortunately often see a resurgence of the disease. Therefore, researchers are looking for new immunotherapy approaches, as well as more accurate ways to assess tumors’ response to treatment.

    Immunotherapy has not yet been broadly effective for patients with gastroesophageal cancer. By testing new treatments in patients prior to surgery, we can make these powerful observations linking treatment-induced molecular changes with survival outcomes, thus accelerating the development of different immunotherapy approaches for our patients.”


    Vincent Lam, M.D., senior study co-author, director of the Esophageal Cancer Research Program and an assistant professor of oncology at Johns Hopkins

    The trial included 32 patients with operable esophageal or gastroesophageal junction cancer, who received nivolumab either alone or in combination with relatlimab prior to and during their standard treatment of chemotherapy and radiation. The drugs tested are both immune checkpoint inhibitors, which prevent cancer cells from dampening the body’s anti-cancer immune response. Researchers used liquid biopsies -; tests that monitor trace levels of tumor DNA shed into the bloodstream -;at different timepoints during treatment. They also measured levels of tumor-recognizing T cells and other components of tumor-specific immune responses.

    About 40% of those in the nivolumab arm and 21.4% in the combination arm had a pathological complete response, meaning there was no evidence of cancer at the time of surgery. Over half of patients in both arms had a major pathological response, meaning less than 10% of cancer cells were remaining at the time of surgery.

    “Historically, about two-thirds of patients treated with standard chemoradiation prior to surgery are alive after two years,” Lam says. “In our study, some 72.5% of participants had no signs of cancer and 82.6% were still living after two years. Notably, patients with undetectable ctDNA at different timepoints following immunotherapy had significantly longer cancer-free survival.” 

    The findings “open the door for more personalized treatment,” says lead study author Ronan Kelly, M.D., M.B.A., chief of oncology at Baylor Scott & White Health – North Texas. Kelly was at Johns Hopkins at the time of the study. “We can either de-escalate or intensify the treatment for patients who have gone through the standard protocol,” he says. “If we see ctDNA is still there, and they don’t have robust T cell response, these are the patients who may benefit most from additional treatment.”

    The study adds to a growing collection of evidence showing the value of molecular readouts like ctDNA to assess response to therapy and guide future treatment plans. For example, another recent study from Anagnostou’s lab, along with a ctDNA-adaptive clinical trial led by Johns Hopkins investigators, showed that ctDNA clearance can predict the success of immunotherapy treatment in patients with advanced lung cancer.

    “You can imagine that liquid biopsies may be used to capture and monitor cancer spread in the body and determine tumor regression across all types of cancers and therapies. There’s ever-growing evidence to support the use of ctDNA in the full range of the cancer care continuum,” says Anagnostou. “We think it’s the future.”

    Additional study co-authors were Blair Landon, Dipika Singh, Jenna Canzoniero, Archana Balan, Russell Hales, K Ranh Voong, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Kristen Marrone, Gavin Pereira, Nisha Rao, Aryan Borole, Katerina Karaindrou, Zineb Belcaid, James White, Suqi Ke, Eun Ji Shin, Elizabeth Thompson, Kellie Smith, Chen Hu and Josephine Feliciano of Johns Hopkins. Experts from the Allegheny Health Network Cancer Institute also contributed to the work.

    The study was supported by Bristol Myers Squibb. Translational work was supported in part by the National Institutes of Health (grants CA121113, R37 CA251447), the Cancer Research Institute, Torrey Coast Foundation GEMINI CLIP Award, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, and the Conquer Cancer Foundation of ASCO Career Development Award.

    Source:

    Journal reference:

    Kelly, R. J., et al. (2024). Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature Medicine. doi.org/10.1038/s41591-024-02877-z.

    [ad_2]

    Source link

  • Study uncovers how APOBEC enzymes drive cancer mutations

    Study uncovers how APOBEC enzymes drive cancer mutations

    [ad_1]

    A research team led by the University of California, Irvine has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumor genomes, offering potential new targets for intervention strategies.

    The study, published today online in the journal Nature Communications, describes how the researchers identified the process by which APOBEC3A and APOBEC3B detect specific DNA structures, resulting in mutations at distinct positions within the tumor genome.

    It’s critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis. Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly.”


    Rémi Buisson, UCI assistant professor of biological chemistry, corresponding author 

    In this study, graduate student Ambrocio Sanchez and postdoctoral fellow Pedro Ortega, both in Buisson’s laboratory at the UCI School of Medicine, developed a new method to characterize the particular kind of DNA modified by APOBEC3A and APOBEC3B. It revealed that the two enzymes do not recognize the same DNA sequences and structures within the genomes of cancer cells. Based on this observation, an innovative approach utilizing these unique target preferences was employed to classify cancer patients who had accumulated mutations caused by each enzyme.

    “The next steps are to investigate whether mutations caused by these enzymes lead to various types of therapy resistance. It’s also critical to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent mutations from forming. Our findings could, in the future, help to assess patient risk before treatment and suppress tumor evolution using the appropriate drug therapy,” Buisson said.

    Other team members included undergraduate and graduate students and postdoctoral fellows from UCI, Harvard Medical School, the University of Southern California, the University of Texas at San Antonio and the University of Minnesota.

    This work was supported by the National Institutes of Health’s Research Supplements to Promote Diversity in Health-Related Research program under award R37-CA252081-S; California Institute for Regenerative Medicine stem cell biology training grant TG2-01152; European Molecular Biology Organization postdoctoral fellowship ALTF 213-2023; Cancer Prevention and Research Institute of Texas research training award RP 170345 and Recruitment of Established Investigators award CPRIT RR220053; the National Cancer Institute under awards R37-VA252081 and P01-CA234228; the National Institute of Allergy and Infectious Diseases under award R01 AI150524; and access to UCI’s Genomics Research and Technology Hub, affiliated with the Chao Family Comprehensive Cancer Center, under grant P30-CA062203.

    Source:

    University of California – Irvine

    Journal reference:

    Sanchez, A., et al. (2024). Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes. Nature Communications. doi.org/10.1038/s41467-024-45909-5.

    [ad_2]

    Source link

  • Scientists aim to understand why T cells do not sustain energy in tumors

    Scientists aim to understand why T cells do not sustain energy in tumors

    [ad_1]

    T cells are often called “assassins” or “killers” because they can orchestrate and carry out missions to hunt down bacteria, viruses, and cancer cells throughout the body. Mighty as they may be, recent research has shown that once T cells infiltrate the environment of a solid tumor, they lose the energy needed to combat the cancer.

    A research team led by Jessica Thaxton, PhD, MsCR, associate professor of cell biology and physiology and co-leader of the Cancer Cell Biology Program at the UNC Lineberger Comprehensive Cancer Center, aimed to understand why T cells do not sustain energy in tumors. Using their expertise in tumor immunity and metabolism, the Thaxton Lab, led by the Katie Hurst, MPH, and 4th year graduate student Ellie Hunt, found that a metabolic enzyme called Acetyl-CoA Carboxylase (ACC) causes T cells to store fat rather than burning fat for energy.

    Our discovery fills a long-standing gap in knowledge regarding why T cells in solid tumors don’t appropriately generate energy. We inhibited the expression of ACC in mouse cancer models, and we observed that T cells were able to persist much better in solid tumors.”


    Jessica Thaxton, PhD, MsCR, associate professor of cell biology and physiology and co-leader of the Cancer Cell Biology Program at the UNC Lineberger Comprehensive Cancer Center

    The new findings and immunotherapeutic strategies, which were published in Cell Metabolism, could be used to make multiple types of T-cell therapies more effective for patients, possibly encompassing both checkpoint and chimeric antigen receptor (CAR) T-cell therapies.

    In the field of cancer immunotherapy, it has long been known that T cells are not able to create their cellular energy, called adenosine triphosphate or ATP, when they are inside of a solid tumor.

    In 2019, Thaxton’s lab studied a T cell with optimal antitumor function. In a publication in Cancer Immunology Research, Hurst and Thaxton used a proteomics screen to identify enzymes associated with the optimal antitumor metabolism of these T cells. Through this screen, the two discovered that ACC expression may limit the ability of T cells to make ATP in tumors. ACC, a key molecule that is involved in many metabolic pathways, blocks cells from breaking down fat and using it as fuel for energy in mitochondria.

    “Acetyl-CoA carboxylase can drive the balance between storing lipids versus breaking down those lipids and feeding them into the citric acid cycle for energy,” said Thaxton. “If ACC is flipped ‘on’, cells generally store lipid. If ACC is ‘off’, cells tend to use the lipid in their mitochondria to make ATP.”

    Using Hunt’s expertise in confocal imaging, the research team was able to observe lipid stores in T cells isolated from multiple types of cancers. The observation, as well as other experiments, confirmed the team’s hypothesis that T cells were storing lipids instead of breaking them down.

    Thaxton’s team then used CRISPR Cas9-mediated gene deletion to see what would happen if they “deleted” ACC from the picture. There was a rapid reduction in the amount of lipid storage in T cells, and the team was able to visualize fat relocating to the mitochondria to be used to generate energy.

    Thaxton now hypothesizes that T cells may need a “delicate balance” of lipids to persist in solid tumors with a certain amount of lipid dedicated to cancer cell assassination and low levels of fats being maintained in stores.

    The latest findings could prove to be useful in enhancing chimeric antigen receptor (CAR) T-cell therapies. This cutting-edge technology takes T cells out of cancer patients, modifies them in the lab to hunt down tumor cells, and then re-infuses the cells to fight the patient’s cancer. Preliminary data from Thaxton’s lab demonstrates that even the manufactured T cells contain excess lipid stores.

    The lab is starting to look in patient samples to understand how researchers can possibly flip the ACC metabolic switch directly in patient tumors, negating the need to take out and reinfuse cells back into the body. But researchers must first determine how this could affect other immune cell populations in the body, such as macrophages.

    Source:

    University of North Carolina Health Care

    Journal reference:

    Hunt, E. G., et al. (2024). Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment. Cell Metabolism. doi.org/10.1016/j.cmet.2024.02.009

    [ad_2]

    Source link

  • BU study reveals key to combating high-risk neuroblastoma

    BU study reveals key to combating high-risk neuroblastoma

    [ad_1]

    The MYCN oncoprotein (proteins related to the growth of cancer cells) plays a key role in starting, advancing and making it difficult to treat various human cancers. When MYCN is overactive, especially in high-risk neuroblastoma (childhood cancer often found in the adrenal glands), the tumors become less responsive to immunotherapy-;a treatment that uses the body’s immune system to fight cancer. Still, recognition of this problem has not led to any effective strategies to tackle this problem.

    In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers found that MYCN selectively increases the levels of a signaling molecule, CKLF, in neuroblastoma cells to suppress anti-tumor immune responses and promote tumor aggressiveness.

    As scientists, we are looking for ways to make these less responsive tumors more receptive to immunotherapy to increase its effectiveness. Understanding how tumor cells utilize this molecule to communicate with immune cells will facilitate the development of effective immunotherapeutic strategies to provide more effective treatments with fewer toxicities for children with high-risk neuroblastoma.”


    Hui Feng, MD, PhD, corresponding author, associate professor of pharmacology, physiology & biophysics, Boston University School of Medicine

    The researchers studied an experimental model, clinical patient samples, and in-vitro cell culture. The experimental models of neuroblastoma with and without overexpression of the signaling molecule, CKLF, were compared for their ability to increase tumor aggression through the suppression of anti-tumor immune responses.

    According to Xiaodan Qin, PhD, the first author of the study and a research scientist in the Feng Lab, the research is critical to understanding the mechanisms by which tumor cells induce a tumor microenvironment that compromises the function of immune cells, and it uncovered additional therapeutic approaches to evoke anti-tumor immune responses. “The long-term goal of this research is to uncover effective drugs that are much less toxic than chemotherapy and radiotherapy for treating high-risk neuroblastoma and perhaps other types of MYCN-driven childhood cancers,” Feng says.

    The findings appear online in Science Advances.

    Source:

    Boston University School of Medicine

    Journal reference:

    Qin, X., et al. (2024). CKLF instigates a “cold” microenvironment to promote MYCN-mediated tumor aggressiveness. Science Advances. doi.org/10.1126/sciadv.adh9547.

    [ad_2]

    Source link

  • Machine learning classifier reduces the time to identify personalized tumor reactive T cell receptors

    Machine learning classifier reduces the time to identify personalized tumor reactive T cell receptors

    [ad_1]

    Making a personalized T cell therapy for cancer patients currently takes at least six months; scientists at the German Cancer Research Center (DKFZ) and the University Medical Center Mannheim have shown that the laborious first step of identifying tumor-reactive T cell receptors for patients can be replaced with a machine learning classifier that halves this time.

    Personalized cellular immunotherapies are considered promising new treatment options for various types of cancer. One of the therapeutic approaches currently being tested are so-called “T-cell receptor transgenic T-cells”. The idea behind this: immune T cells from a patient are equipped in the laboratory to recognize the patient’s own unique tumor, and then reinfused in large numbers to effectively kill the tumor cells.

    The development of such therapies is a complicated process. First, doctors isolate tumor-infiltrating T cells (TILs) from a sample of the patient’s tumor tissue. This cell population is then searched for T-cell receptors that recognize tumor-specific mutations and can thus kill tumor cells. This search is laborious and has so far required knowledge of the tumor-specific mutations that lead to protein changes that are recognized by the patients’ immune system. During this time the tumor is constantly mutating and spreading, making this step a race against time.

    “Finding the right T cell receptors is like looking for a needle in a haystack, costly and time-consuming,” says Michael Platten, Head of Department at the DKFZ and Director of the Department of Neurology at the University Medical Center Mannheim. “With a method that allows us to identify tumor-reactive T-cell receptors independently of knowledge of the respective tumor epitopes, the process could be considerably simplified and accelerated.”

    A team led by Platten and co-study head Ed Green has now presented a new technology that can achieve precisely this goal in a recent publication. As a starting point, the researchers isolated TILs from a melanoma patient’s brain metastasis and performed single cell sequencing to characterize each cell. The T cell receptors expressed by these TILs were then individually tested in the lab to identify those that were recognized and killed patient tumor cells. The researchers then combined these data to train a machine learning model to predict tumor reactive T cell receptors. The resulting classifier could identify tumor reactive T cells from TILs with 90% accuracy, works in many different types of tumor, and accommodates data from different cell sequencing technologies.

    predicTCR enables us to cut the time it takes to identify personalized tumor reactive T cell receptors from over three months to a matter of days, regardless of tumor type.”


    Ed Green, co-study head 

    “We are now focusing on bringing this technology into clinical practice here in Germany. To finance further development, we have founded the biotech start-up Tcelltech,” adds Michael Platten. “predicTCR is one of the key technologies of this new DKFZ spin-off.”

    C.L. Tan, K. Lindner, T. Boschert, Z. Meng, A. Rodriguez Ehrenfried, A. De Roia, G. Haltenhof, A. Faenza, F. Imperatore, L. Bunse, J.M. Lindner, R.P. Harbottle, M. Ratliff, R. Offringa, I. Poschke, M. Platten and E.W. Green: Tumor-reactive T-cell receptors are rapidly identified from lymphocyte scRNA-seq data.

    Source:

    German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

    Journal reference:

    Tan, C. L., et al. (2024). Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy. Nature Biotechnology. doi.org/10.1038/s41587-024-02161-y

    [ad_2]

    Source link

  • DNA origami vaccine DoriVac paves way for personalized cancer immunotherapy

    DNA origami vaccine DoriVac paves way for personalized cancer immunotherapy

    [ad_1]

    Therapeutic cancer vaccines are a form of immunotherapy in the making that could not only destroy cancer cells in patients, but keep a cancer from coming back and spreading. Multiple therapeutic cancer vaccines are being studied in clinical trials, but despite their promise, they are not routinely used yet by clinical oncologists to treat their patients. 

    The central ingredient of therapeutic cancer vaccines is antigens, which are preferentially produced or newly produced (neoantigens) by tumor cells and enable a patient’s immune system to search and destroy the cancerous cells. In most cases, those antigens cannot act alone and need the help of adjuvant molecules that trigger a general alarm signal in immune cells known as antigen-presenting cells (APCs). APCs internalize both antigen and adjuvant molecules and present the antigens to different types of T cells. Those T cells then launch an immediate attack against the tumor, or preserve a longer-lasting memory of the tumor for future defense.

    A cancer vaccine’s effectiveness depends on the level and duration of the “alarm” its adjuvants can ring in APCs. Previously, researchers found that delivering adjuvant and antigen molecules to APCs simultaneously using nanostructures like DNA origami can increase APC activation. However, none of these approaches systematically investigated how the number and nanoscale arrangement of adjuvant molecules affect downstream tumor-directed immunity. 

    Now, a research team at the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), and Korea Institute of Science and Technology (KIST) has created a DNA origami platform called DoriVac, whose core component is a self-assembling square block-shaped nanostructure. To one face of the square block, defined numbers of adjuvant molecules can be attached in highly tunable, nanoprecise patterns, while the opposite face can bind tumor antigens. The study found that molecules of an adjuvant known as CpG spaced exactly 3.5 nanometers apart from each other resulted in the most beneficial stimulation of APCs that induced a highly-desirable profile of T cells, including those that kill cancer cells (cytotoxic T cells), those that cause beneficial inflammation (Th-1 polarized T cells), and those that provide a long-term immune memory of the tumor (memory T cells). DoriVac vaccines enabled tumor-bearing mice to better control the growth of tumors and to survive significantly longer than control mice. Importantly, the effects of DoriVac also synergized with those of immune checkpoint inhibitors, which are a highly successful immunotherapy that is already widely used in the clinic. The findings are published in Nature Nanotechnology.

    “DoriVac’s DNA origami vaccine technology merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes,” said Wyss Core Faculty member William Shih, Ph.D., who led the Wyss Institute team together with first-author Yang (Claire) Zeng, M.D., Ph.D. “We envision that in the future, antigens identified in patients with different types of tumors could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalized cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies.”

    Shih is also a Professor at HMS and DFCI’s Department of Cancer Biology and, as some of the other authors, a member of the NIH-funded cross-institutional “Immuno-engineering to Improve Immunotherapy” (i3) Center based at the Wyss. 

    DNA origami rationale

    The CpG adjuvant is a synthetic strand of DNA made up of repeated CpG nucleotide motifs that mimic the genetic material from immune cell-invading bacterial and viral pathogens. Like its natural counterparts, CpG adjuvants bind to a “danger receptor” called TLR9 in immune cells, which in turn induces an inflammatory (innate) immune response that works in concert with the antigen-induced (adaptive) immune response. 

    “We knew from previous work that to trigger strong inflammatory responses, TLR9 receptors need to dimerize and aggregate into multimeric complexes binding to multiple CpG molecules. The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesized we could mirror with DNA origami structures presenting precisely spaced CpG molecules,” explained Zeng, who was an Instructor in Medicine at the time of the study and now is a senior scientist at DFCI and Harvard Medical School (HMS). In addition to Shih, Zeng was also mentored on the project by senior authors Ju Hee Ryu, Ph.D., a Principal Researcher at KIST, and Wyss Founding Core Faculty member David Mooney, Ph.D., who also is Professor at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and one of the i3 Center’s Principal Investigators. 

    Zeng and the team fabricated DoriVac vaccines in which different numbers of CpG strands were spaced at 2.5, 3.5, 5, or 7 nanometers apart from each other on one face of the square block, and a model antigen was attached to the opposite face. They protected their structures from being degraded in the body using a chemical modification method that Shih’s group had developed earlier. When internalized by different types of APCs, including dendritic cells (DCs), which orchestrate tumor-directed T cell responses, the DoriVac vaccines improved the uptake of antigens compared to controls consisting of free antigen molecules. A CpG spacing of 3.5 nanometers produced the strongest and most beneficial responses in APCs, and significantly outperformed a control vaccine containing only free CpG molecules. “We were excited to find that the DoriVac vaccine preferentially induced an immune activation state that supports anti-tumor immunity, which is what researchers generally want to see in a good vaccine,” said Zeng. 

    Besides spacing, the numbers of CpG molecules in DoriVac vaccines also mattered. The team tested vaccines containing between 12 to 63 optimally spaced CpG molecules and found that 18 CpG molecules provided the best APC activation. This meant that their approach can also help limit the dosage of CpG molecules and thus minimize commonly observed toxic side effects observed with adjuvants.

    Gained in (tumor) translation

    Importantly, these in vitro trends translated to in vivo mouse tumor models. When prophylactically injected under the skin of mice, DoriVac vaccines accumulated in the closest lymph nodes where they stimulated DCs. A vaccine loaded with a melanoma antigen prevented the growth of subsequently injected aggressive melanoma cells. While all control animals had succumbed to the cancer by day 42 of the experiment, DoriVac-protected animals all were alive. DoriVac vaccines also inhibited tumor growth in mice in which the formation of melanoma tumors was already underway, with a 3.5 nanometer spacing of 18 CpG molecules again providing maximum effects on DC and T cells, and the strongest reduction in tumor growth.

    Next, the team asked whether DoriVac vaccines could also boost immune responses produced by small “neoantigens” emerging in melanoma tumors. Neoantigens are ideal targets because they are exclusively made by tumor cells. However, they often are not very immunogenic themselves, which make highly effective adjuvants an important component in neoantigen vaccines. A DoriVac vaccine customized with four neoantigens enabled the researchers to significantly suppress growth of the tumor in mice that produced the neoantigens.

    Finally, the researchers asked whether DoriVac could synergize with immune checkpoint therapy, which reactivates T cells that have been silenced in tumors. In mice, the two therapies combined resulted in the total regression of melanoma tumors, and prevented them from growing back when the animals were exposed to the same tumor cells again four months later. The animals had built up an immune memory of the tumor. The team obtained a similar vaccination efficiency in a mouse lymphoma model.

    We think that DoriVac’s value for determining a sweet spot in adjuvant delivery and enhancing the delivery and effects of coupled antigens can pave the way to more effective clinical cancer vaccines for use in patients with a variety of cancers.”


    Yang (Claire) Zeng, M.D., Ph.D., First Author

    The team is currently translating the DoriVac platform toward its clinical application, which is supported by the study’s assessment of vaccine distribution and vaccine-directed antibodies in mice, as well as cytokines produced by immune cells in response to the vaccines in vivo. 

    “The DoriVac platform is our first example of how our pursuit of what we call Molecular Robotics – synthetic bioinspired molecules that have programmable shape and function – can lead to entirely new and powerful therapeutics. This technology opens an entirely new path for development of designer vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.

    Other authors on the study are Olivia Young, Christopher Wintersinger, Frances Anastassacos, James MacDonald, Giorgia Isinelli, Maxence Dellacherie, Miguel Sobral, Haiqing Bai, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas Ferrante, Derin Keskin, Geoffrey Fell, Donna Neuberg, Cathrine Wu, and Ick Chan Kwon. The study was funded by the Wyss Institute’s Validation Project and Institute Project programs, Claudia Adams Barr Program at DFCI, Korean Fund for Regenerative Medicine (award #21A0504L1), Intramural Research Program of KIST (award #2E30840), and National Institutes of Health (under the i3 Center supporting U54 grant (award #CA244726-01).

    Source:

    Wyss Institute at Harvard University

    Journal reference:

    Zeng, Y. C., et al. (2024). Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination. Nature Nanotechnology. doi.org/10.1038/s41565-024-01615-3.

    [ad_2]

    Source link