Targeting Macrophages to Stimulate Anti-Tumor Immunity

Friday, March 13, 2020 -
2:00pm to 3:00pm
The FUNG Auditorium
Judy Varner

Chair, Academic Senate Committee on Privilege and Tenure

Professor of Pathology and Medicine

Moores Cancer Center

University of California, San Diego

Targeting Macrophages to Stimulate Anti-Tumor Immunity

Abstract: 

Macrophages are phagocytic leukocytes that accumulate rapidly in tumors, where they promote immune suppression, tumor growth and resistance to therapy. Strategies to inhibit macrophage accumulation by blocking their recruitment from circulation have had limited therapeutic success. We found that the majority of macrophages in tumors accumulate by proliferation from  tissue resident macrophage progenitors, rather than by trafficking from the circulation. Tissue resident macrophages express signatures of Myc driven proliferation and profound immune suppression that correlate with unfavorable outcomes in cancer patients. By comparison, bone marrow derived macrophages express signatures of inflammation and immune response that correlate with more favorable clinical outcomes. Inhibitory targeting of  macrophage proliferation in tumors promote CD8+T cell recruitment and tumor growth suppression or regression in mouse models of cancer. Additionally, strategies to change macrophage gene expression (repolarization) to promote anti-tumor immune responses have also had some therapeutic success. We have shown that inhibitory targeting of PI3 kinase gamma, a key signaling intermediate in myeloid cells, not only blocks myeloid cell recruitment from the bone marrow but also repolarizes myeloid cells to express large quantities of pro-inflammatory cytokines. Inhibition of PI3Kgamma stimulates T cell activation and memory formation and inhibits fibrosis and tumor progression. These results illustrate that macrophages promote cancer immune suppression and are valuable targets for cancer immune therapy.

Bio: 

Judy Varner is Professor in the Departments of Pathology and Medicine at the University of California, San Diego and a member in the Moores UCSD Cancer Center. She joined the Department of Medicine in 1997 and the Department of Pathology in 2012. Dr. Varner received her undergraduate degree in Chemistry from Duke University, where she was an A.B. Duke and National Merit Scholar and her Ph.D. in Biochemistry from the University of Basel, Switzerland, where she was a Fulbright Fellow. Prior to coming to UCSD, she was a postdoctoral fellow in the Department of Pharmacology at the University of North Carolina at Chapel Hill where she studied integrin signaling in cancer. As a member of Moores Cancer Center, her research has focused on mechanisms regulating angiogenesis and inflammation in cancer. Her work, which recently appeared in journals that include Cancer Cell, Nature and Cancer Discovery, has identified novel mechanisms by which macrophages promote tumor growth and has developed new approaches to treat cancer patients by targeting tumor macrophage signal transduction. Dr. Varner serves as Faculty Mentoring Director in the Department of Pathology at UCSD, as Chair of the UCSD Committee on Privilege and Tenure and has served chair of numerous grant review panels for the NIH and the AACR. Dr. Varner is recipient of the 2017 V Foundation Award for Translational Research, the 2012 AACR-Landon Foundation Innovator Award for International Collaboration and the 2012 Lustgarten Foundation Innovator Award for Pancreatic Cancer Research.