Systems analysis of cell-cell communication networks and immune activity in the melanoma tumor microenvironment
- Systems analysis of cell-cell communication networks and immune activity in the melanoma tumor microenvironment
List of Collaborating Institutions
- Yale University
Salk Institute of Biological Studies
Cancer immunotherapy, which harnesses a patient’s own immune system to fight cancer, has revolutionized cancer treatment. Combination immunotherapy targeting the T cell checkpoint inhibitors PD-1 and CTLA-4 has been particularly effective in treating metastatic melanoma. Despite this success, a significant fraction of melanoma patients remains unresponsive to current checkpoint inhibitor combination therapy, and thus there is an urgent need to identify new targets to treat these patients. However, efforts to identify effective therapeutic targets are limited by our incomplete understanding of the molecular determinants that distinguish an ineffective anti-tumor immune response from an effective one.
The goal of our U01 project is to advance cancer immunotherapy by defining networks of intercellular secreted signals that establish immunological activity in the tumor microenvironment (TME). The rationale for the proposed research is that identifying cell-cell interactions that distinguish immunosuppressive versus immunosupportive TMEs will serve as a roadmap of new targets to test in unresponsive tumors. Our project takes advantage of the availability of single-cell measurements that enable the simultaneous profiling of thousands of cells isolated from tumor microenvironments from mouse models of melanoma and from human melanoma patients. We will computationally analyze these data to construct cell-cell interaction networks between stromal, tumor, and immune cells to identify interactions that maintain immunosuppressive TMEs, and to quantify how these interactions are altered in response to cancer immunotherapy. We will use our models to identify the most important interactions, predict how to target them, and test these predictions experimentally. We are particularly interested in how the functional plasticity of macrophages and other myeloid cells contributes to an immunosuppressive TME in mice and human melanomas. With respect to cancer systems biology, the proposed research is innovative because it will combine new computational methods–for defining cell subsets and network interactions from scRNA-seq data and constructing predictive classification models–with syngeneic mouse melanoma models and human patient samples that are ideally suited to evaluate CIT responses. The proposed research is significant because it will redefine the hallmarks of immune activity in the TME as emergent properties of multiple cell-cell interactions that can be pharmacologically targeted to design immunotherapies that will be effective on non-responding patients.
Kathryn Miller-Jensen, Ph.D.
Kathryn Miller-Jensen, PhD (co-PI) is an Associate Professor of Biomedical Engineering and Molecular, Cellular, and Developmental Biology at Yale University. Dr. Miller-Jensen’s research uses quantitative, systems-level approaches to study intracellular and extracellular signaling networks regulating immune cell functions. Her lab is particularly interested in how variability between single cells impacts immune responses. Research projects in the lab focus on the regulation of macrophage activation in response to pathogenic stimulation and within tumor microenvironments. She is a member of the Yale Cancer Center and the Systems Biology Institute.
Marcus Bosenberg, M.D., Ph.D.
Marcus Bosenberg, MD, PhD (co-PI) is a Professor of Dermatology, Pathology, and Immunobiology at Yale University. He is a physician-scientist who directs a leading melanoma research laboratory and is a practicing dermatopathologist at Yale Dermatopathology through Yale Medicine. In his research, Dr. Bosenberg studies the genetics and cellular changes that result in melanoma, the leading cause of skin cancer deaths. His laboratory has developed several widely utilized mouse models in order to study how melanoma forms and progresses, to test new melanoma therapies, and how the immune system can be stimulated to fight melanoma. He works to translate basic scientific findings into improvements in melanoma diagnosis and therapy. Dr. Bosenberg also serves as Interim Director of the Yale Center for Immuno-Oncology, and Director of the Yale SPORE in Skin Cancer.
Susan Kaech, Ph.D.
Susan Kaech, PhD (co-I) is Professor and Director of the NOMIS Center for Immunobiology and Microbial Pathogenesis at the Salk Institutet for Biological Studies. Dr. Kaech aims to understand how memory T cells are produced during infection and vaccination, how they function and why they can fail to induce long-term immunity, particularly during chronic disease or cancer. Her lab has been a leader in using genetic and molecular tools to identify the genes and signaling molecules involved in generating two specific types of memory T cells, CD4 and CD8, from precursor cells during both acute and chronic viral infections. Dr. Kaech is especially interested in how T cells are metabolically regulated, and how their specialization and function can be altered by the types of nutrients available in infected tissues or in tumors. Related to this, she seeks to learn how T cell behavior is suppressed by tumors, in order to create better therapies for cancer using the body’s own immune system—an innovative and rapidly moving field called cancer immunotherapy.
Harriet Kluger, M.D.
Harriet Kluger, MD (co-I) is a Professor of Medicine (Medical Oncology) at the Yale School of Medicine. Dr. Kluger is a medical oncologist who sees patients with melanoma and renal cell carcinoma. Her research interests focus on developing new drug regimens and biomarkers predictive of response to therapies in melanoma and renal cell carcinoma. She participates in a number of clinical trials studying new agents for the treatment of these diseases, both targeting the immune system and the cancer cell. She runs an active research laboratory that studies tumor and immune cells from patients treated with novel therapies to determine mechanisms of resistance to therapy and mediators of toxicity from immune checkpoint inhibitors. The laboratory also conducts pre-clinical studies to improve treatment regimens for patients with melanoma, renal cell carcinoma or brain metastasis. Dr. Kluger also serves as Director of the Yale Immuno-Oncology Training Program and the Deputy Section Chief for Medical Oncology.