Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.
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2013-09
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Abstract
Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.
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Hanks, Brent A, Alisha Holtzhausen, Katherine S Evans, Rebekah Jamieson, Petra Gimpel, Olivia M Campbell, Melissa Hector-Greene, Lihong Sun, et al. (2013). Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest, 123(9). pp. 3925–3940. 10.1172/JCI65745 Retrieved from https://hdl.handle.net/10161/13297.
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Scholars@Duke
Brent A. Hanks
We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of immunotherapies while also developing predictive biomarkers to better guide the management of cancer patients with these agents. We strive to translate our understanding of the fundamental biochemical and metabolic pathways within the tumor microenvironment that are critical for driving immune evasion and resistance into early phase clinical trial testing.
Our work utilizes a variety of techniques and methodologies that span the breadth of basic biological research. This work integrates studies based on both 1) transgenic mouse tumor models that are monitored using bioluminescence and micro-CT imaging and 2) a variety of clinical specimens.
Our current areas of focus include:
- Investigating mechanisms of adaptive or acquired immunotherapy resistance in cancer
- Studying the relationship between EMT pathways and immunotherapy resistance.
- Elucidating mechanisms of dendritic cell tolerization in the tumor microenvironment and how these processes may contribute to immunotherapy resistance
- Development of novel pharmacologic and genetic strategies to overcome immunotherapy resistance
- Investigating mechanisms contributing to select immunotherapy-associated toxicities
Andrew Benjamin Nixon
Dr. Andrew Nixon is Professor of Medicine in the Department of Medicine/Division of Medical Oncology at Duke University. He holds a BS in chemistry from Miami University, a PhD in biochemistry from Wake Forest University, and an MBA with a focus on healthcare management from Duke University/Fuqua School of Business. He is a nationally recognized expert in the development of cancer biomarkers and correlative science, with extensive experience leading large multi-center biomarker analyses. Dr. Nixon serves in various leadership roles within the National Cancer Institute (NCI), working with diverse multi-disciplinary teams focused on improving cancer patient outcomes through biomarker science. He serves as the national co-chair for the NCI Core Correlative Sciences Committee which adjudicates the use of biospecimens collected throughout the NCI National Clinical Trial Network (NCTN). Within the NCI-NCTN Alliance cooperative group, Dr. Nixon has multiple leadership positions including serving on the Alliance Board of Directors, co-chair of the Immuno-Oncology Committee, co-chair for Gastrointestinal Correlative Research, and has been an executive member of the Translational Research Program since its inception. Additionally, within the NCI-NCTN NRG cooperative group, he serves as a member of the Gynecologic Translational Science Committee and on the Gynecological Oncology Group - Partners Investigator Council Translational Research Subcommittee. Dr. Nixon is an American Society for Clinical Oncology (ASCO) Ambassador and has chaired various committees and led scientific and educational sessions at national conferences. Recently, Dr. Nixon has focused his research on cellular senescence and biomarkers of aging and early carcinogenesis. He serves as Principal Investigator for a large multi-center NIH grant to develop high-resolution tissue maps and biomarkers of cellular senescence as a part of the Senescence Network (SenNet) Consortium.
Georgia Marie Beasley
Dr. Beasley is an associate professor of surgery in the division of Surgical Oncology at Duke University with a secondary appointment as associate professor in the department of medicine. After playing 3 years in the women’s NBA, she began medical school. She obtained her MD (2008) and Masters of Health Science in clinical research (2010) from Duke University School of Medicine. She then completed general surgical residency at Duke University in 2015, during which time she was awarded a traineeship under a long-standing Surgical Oncology T32 grant. She then completed a fellowship in complex surgical oncology at the Ohio State University in 2017. She returned to Duke in 2017 as a faculty member. In 2019, she became co-director of the Duke Melanoma Program.
Dr. Beasley is a surgeon scientist with active involvement in clinical and translational research. Her main clinical and research interests include immunologic aspects of melanoma including oncolytic viral therapy. She is principal investigator of over 10 therapeutic clinical trials in melanoma including novel intratumoral therapies. Her research focuses on the role of innate immunity in the anti-tumor response. She has authored over 100 publications centered on melanoma. She has received multiple internal and external funding including the Society of Surgical Oncology’s Young Investigator Award, NIH K08 mentored physician scientist award, and Melanoma Research Alliance Grant.. Most recently she was selected to Duke Medical School’s Alpha Omega Alpha and received the American Society for Clinical Investigation Young Physician-Scientist Award.
Takuya Osada
Michael Aaron Morse
We are studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on adoptive transfer of tumor and viral antigen-specific T cells.
Our current clinical trials include phase I and II studies of immunotherapy for: patients with metastatic malignancies expressing CEA, pancreatic cancer, colorectal cancer, breast cancer, and ovarian cancer, and leukemias following HSCT. My clinical area of expertise is in gastrointestinal oncology, in particular, the treatment of hepatic malignancies, and malignant melanoma.
Key words: dendritic cells, immunotherapy, vaccines, T cells, gastrointestinal oncology, melanoma, hepatoma
Herbert Kim Lyerly
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.