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The James P. Allison Institute at The University of Texas MD Anderson Cancer Center today announced the establishment of its scientific advisory board to provide strategic guidance and evaluation of its research portfolio and programs. The 11-person advisory board, which brings together global leaders in immunotherapy and immunobiology, will hold its inaugural meeting today.
The advisory board will be co-chaired by Robert Schreiber, Ph.D., the Andrew M. and Jane M. Bursky Distinguished Professor of Pathology and Immunology at Washington University School of Medicine, and Elaine Mardis, Ph.D., co-executive director of the Steve and Cindy Rasmussen institute for Genomic Medicine at Nationwide Children’s Hospital and professor of Pediatrics at The Ohio State University College of Medicine.
“As we work to make scientific breakthroughs that bring us a deeper understanding of immunobiology, it is critical that we engage with the world’s leading experts,” said Padmanee Sharma, M.D., Ph.D., director of Scientific Programs for the Allison Institute and professor of Genitourinary Medical Oncology and Immunology at MD Anderson. “The experience and insight from this stellar group of physicians and scientists will be invaluable in steering us toward our ultimate goal of bringing the benefits of immunotherapy to all patients.”
The Allison Institute was launched to foster groundbreaking scientific research that will integrate immunobiology across disciplines. With exceptional discovery, translational and clinical research, the institute will develop novel and synergetic therapies that enable cures for more patients.
The institute is led by Director James P. Allison, Ph.D., regental chair of Immunology, together with Sharma and Director of Operations Raghu Kalluri, M.D., Ph.D., chair of Cancer Biology.
Members of the scientific advisory board include:
- Mark Dawson, M.D., Ph.D., is a clinician-scientist and an associate director of the Peter MacCallum Cancer Centre in Melbourne, Australia. He also is a professor at the University of Melbourne, the Sir Edward Dunlop Fellow for the Cancer Council of Victoria and a Howard Hughes Medical Institute International Research Scholar. Dawson’s research is focused on studying epigenetic regulation in normal development and cancer. His research has helped identify several first-in-class epigenetic therapies resulting in various clinical trials around the world. Among several honors, Dawson was elected to the Australian Academy of Science and the Australian Academy of Health and Medical Sciences.
- Philip Greenberg, M.D., is professor and head of the Program in Immunology at Fred Hutchinson Cancer Center in Seattle, Washington, and he holds the Rona Jaffe Foundation Endowed Chair. Greenberg is an internationally recognized expert in cancer immunotherapy and president-elect of the American Association for Cancer Research. His early discoveries showed how to target diseases using T cells and developed the technology for generating antigen-specific T cells ex vivo for cell therapy, which helped drive the field forward. Greenberg continues to lead efforts to develop and test new strategies to genetically reprogram T cells and to use synthetic biology to even more effectively target many cancer types.
- Marcia Haigis, Ph.D., is professor of Cell Biology and director of Gender Equity for Faculty in Science at Harvard Medical School. She is an active member of the Dana Farber/Harvard Cancer Center, the Paul F. Glenn Center for Biology of Aging Research and the Ludwig Center at Harvard Medical School. Haigis’ research has made fundamental contributions to the understanding of how mitochondria mediate metabolic reprogramming in cancer and contribute to tumor and immune interactions in the tumor microenvironment. She is a recipient of numerous awards and was chosen as a National Academy of Medicine Emerging Leader in Health and Medicine.
- Elaine Mardis, Ph.D., is co-executive director of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital in Columbus, Ohio, and holds the Rasmussen Nationwide Foundation Endowed Chair of Genomic Medicine. She also is professor of Pediatrics at The Ohio State University College of Medicine, a member of the National Academy of Medicine and past president of the American Association for Cancer Research. Mardis is an internationally recognized expert in cancer genomics and immunogenomics, with interests in the integrated characterization of cancer genomes, defining DNA-based interactions and RNA-based pathways and immune microenvironments that lead to cancer onset and progression, with a focus on pediatric cancers and precision oncology.
- Diane Mathis, Ph.D., is professor of Immunology at Harvard Medical School and holds the Morton Grove-Rasmussen Chair of Immunohematology. She is an active member of the Committee on Immunology at Harvard Medical School, the Broad Institute, the Dana-Farber/Harvard Cancer Center and the Harvard Stem Cell Institute. Mathis’ research on T cell differentiation and tolerance/autoimmunity seeks to understand these processes at a mechanistic level and discover how they influence a variety of human diseases. She is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.
- Miriam Merad, M.D., Ph.D., is the director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai and the director of the Human Immune Monitoring Center at Mount Sinai in New York City. She is an internally acclaimed physician-scientist and leader in the fields of dendritic cell and macrophage biology, focusing on their contributions to human disease. Merad has identified new subsets of both macrophages and dendritic cells, both with key roles in regulating the anti-tumor immune response. She is now working to develop therapies targeting these unique cell populations in cancer and other conditions. For her contributions to the field, Merad was elected to the National Academy of Sciences in 2020.
- Kunle Odunsi, M.D., Ph.D., is director of the University of Chicago Medicine Comprehensive Cancer Center and dean for Oncology, Biological Services Division at the University of Chicago. Odunsi is responsible for strategic oversight of all programmatic aspects of cancer at the University of Chicago, including the three primary missions of research, patient care and education. His research in tumor immunology and immunotherapy focuses on the mechanisms of immune recognition in ovarian cancer and on the development of therapies targeting tumor antigens. Odunsi is a member of the National Academy of Medicine.
- Robert Schreiber, Ph.D., is the Andrew M. and Jane M. Bursky Distinguished Professor of Pathology and Immunology and director of the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University School of Medicine in St. Louis, Missouri. He is a tumor immunologist and cytokine biologist who has focused primarily on interferon-gamma biology, seeking to understand the mechanisms underlying natural and therapeutically induced immune responses to developing and established cancers. Schreiber demonstrated that the immune system can prevent tumor outgrowth, induce tumor dormancy and sculpt tumor immunogenicity — a process he named cancer immunoediting. Schreiber is a member of the National Academy of Sciences and the American Academy of Arts and Sciences along with many other honors.
- Phillip Sharp, Ph.D., is an institute professor at the Massachusetts Institute of Technology and member of the Department of Biology at the Koch Institute for Integrative Cancer Research at MIT. His research interests have centered on the molecular biology of gene expression relevant to cancer and the mechanisms of RNA splicing. His landmark discoveries provided the first indications of “discontinuous genes” in mammalian cells, changing the understanding of gene structure and earning Sharp the 1993 Nobel Prize in Physiology or Medicine. Sharp also is a member of the National Academy of Sciences, the National Academy of Medicine and the American Academy of Arts and Sciences, in addition to many other honors.
- Karen Vousden, Ph.D., is a group leader at the Francis Crick Institute in London, England and former chief scientist for Cancer Research UK. Her research has made contributions to the understanding of how the tumor suppressor p53 is regulated and how it functions to control cancer progression. Vousden revealed an unexpected ability of p53 to help cells adapt and survive under transient periods of serine starvation, leading her to focus on cancer cell metabolism and on the role of oxidative stress and one carbon metabolism in cancer development and metastatic progression. Among numerous honors, Vousden is an international member of the National Academy of Sciences and the American Academy of Arts and Sciences.
- Catherine J. Wu, M.D., is the leader of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute in Boston, Massachusetts. She has initiated an integrated program of research and clinical activities that focuses on dissecting the basis of effective anti-tumor immunity. Her laboratory has focused on the use of genomics-based approaches to discover immunogenic antigen targets and to understand the molecular basis of therapeutic response and resistance. Wu is a member of the National Academy of Medicine and has received numerous other awards.
Cancer cells produce small amounts of their own form of collagen, creating a unique extracellular matrix that affects the tumor microbiome and protects against immune responses, according to a new study by researchers at The University of Texas MD Anderson Cancer Center. This abnormal collagen structure is fundamentally different from normal collagen made in the human body, providing a highly specific target for therapeutic strategies.
This study, published today in Cancer Cell, builds upon previously published findings from the laboratory of Raghu Kalluri, M.D., Ph.D., chair of Cancer Biology and director of operations for the James P. Allison Institute, to bring a new understanding of the unique roles of collagen made by fibroblasts and by cancer cells.
“Cancer cells make an atypical collagen to create their own protective extracellular matrix that helps their proliferation and their ability to survive and repel T cells. It also changes the microbiome in a way that helps them thrive,” said Kalluri, senior author on the study. “Uncovering and understanding this unique adaptation can help us target more specific treatments to combat these effects.”
Type I collagen, the most abundant protein in the body, is produced by fibroblasts and found mostly in bones, tendons and skin. Previously, collagen in tumors was believed to promote cancer development, but Kalluri’s laboratory showed that it likely plays a protective role in suppressing pancreatic cancer progression.
In its normal form, collagen is a heterotrimer consisting of two α1 chains and one α2 chain, which assemble to form a triple-helix structure as part of the extracellular matrix. However, when studying human pancreatic cancer cell lines, the researchers discovered the cells expressed only the α1 gene (COL1a1), whereas fibroblasts expressed both genes.
Further analysis revealed that cancer cells have silenced the α2 gene (COL1a2) through epigenetic hypermethylation, resulting in a cancer-specific collagen ‘homotrimer’ made up of three α1 chains.
Loss of cancer-specific collagen reduces cancer progression, could boost anti-tumor immune response
To investigate the real-world effects of this observation, the researchers created knockout mouse models of pancreatic cancer with COL1a1 deleted only in cancer cells. Loss of this cancer-specific homotrimer reduced cancer cell proliferation and reprogrammed the tumor microbiome. This led to lower immunosuppression, which was associated with increased T cell infiltration and elimination of cancer cells.
Additionally, these knockout mice responded more favorably to anti-PD1 immunotherapy, suggesting that targeting this cancer-specific collagen could help boost the anti-tumor immune response.
“This discovery illustrates the importance of mouse models, as it was only when we noticed a difference in their survival that we found this abnormal collagen variant existed and was produced specifically by the cancer cells,” Kalluri said. “Because it is generated in such small amounts relative to normal collagen, the homotrimer would have otherwise gone undetected without specific tools to differentiate them.”
Cancer-specific collagen alters the tumor microbiome and immune profile
Given the relationship between the gut and tumor microbiomes and immune responses, the researchers also explored the microbiome in their mouse models. Interestingly, loss of the cancer-specific collagen led to changes in the bacterial composition within the tumor. There was a corresponding decrease in myeloid-derived suppressor cells (MDSCs) and an increase in T cells, contributing to favorable survival outcomes.
These effects were completely reversed by disrupting the microbiome with antibiotics, suggesting that cancer-specific collagen promotes cancer progression by enhancing a tumor-promoting microbiome. This is early evidence that the extracellular matrix directly influences the tumor microbiome, which could help researchers to understand how cancer cells have developed these adaptions against an immune response.
Further investigation clarified some of the mechanisms behind these findings, demonstrating that loss of the cancer-specific collagen increased levels of CXCL16, which attracts T cells, and reduced expression of CXCL5, which attracts MDSCs. Loss of the collagen homotrimer also increased the amount of normal fibroblast collagen in the stroma, which, as Kalluri’s lab previously showed, inhibits tumor progression. These results provide additional evidence that cancer-produced homotrimers affect signal pathways that can alter the tumor immune profile.
Cancer-specific collagen and its receptors represent novel therapeutic targets
The study also found that the abnormal collagen upregulates signal pathways associated with cancer cell proliferation by binding to a surface protein called integrin α3. Indeed, suppressing integrin α3 in vivo increased T cell infiltration and prolonged survival, highlighting this interaction as a very specific target for potential therapeutic strategies.
“No other cell in the normal human body makes this unique collagen, so it offers tremendous potential for the development of highly specific therapies that may improve patient responses to treatment,” Kalluri said. “On many levels, this is a fundamental discovery and a prime example of how basic science unravels important findings that could later benefit our patients.”
While the current study looked specifically at pancreatic cancer, Kalluri noted that collagen homotrimers also are seen in other cancer types, including lung and colon cancers, signifying a possible unifying principle with broad implications for cancer treatment.
This work was supported by the National Cancer Institute (P01CA117969, P30CA016672), the Ergon Foundation, Inc. and the Sid W. Richardson Foundation. A complete list of research support and a full list of collaborating authors, including their disclosures, can be found within the full paper here.