Regulatory T cells and the tumor microenvironment

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PROJECT SUMMARY I have been dissecting the mechanisms of immune regulation for ~27 years, and have been discovering and dissecting immune inhibitory mechanisms in cancer for over 10 years. Cancer immunology and immunotherapy now occupy ~80% of my research and translational focus. This has not only led to numerous cancer-focused high impact papers (11; Nature [1], Cell [1], Nature Immunology [4], Immunity [3], Science Immunology [1]; Cancer Research [1]), with 5 since 2016, but has also facilitated the development of immunotherapeutics targeting LAG3, EBI3 and NRP1 in multiple cancer clinical trials, some in Phase III. Inhibitory mechanisms within the tumor microenvironment (TME) represent major barriers to effective anti-tumor immunity. Although striking efficacy has been reported with inhibitory receptor (IR) blockade, it’s clear that additional inhibitory mechanisms will need to be targeted to substantially improve therapeutic outcome in most tumor types and for most patients. Regulatory T cells (Tregs) are potent inhibitors of anti-tumor immunity. Although Treg ablation results in rapid tumor shrinkage in multiple cancer models, this is not a viable therapeutic approach due to the subsequent severe autoimmune consequences. Thus, novel approaches are needed to limit Treg activity selectively in tumors, combined with a detailed understanding of their mechanism of action. We have previously focused on two main lines of inquiry, with emphasis on mechanisms that are selectively upregulated and impactful within the TME: [a] How do Tregs work in the TME? This led to the discovery of the inhibitory cytokine interleukin-35 (IL-35). [b] What potentiates Treg stability, survival and function? This led to the discovery of the NRP1:SEMA4A axis that controls Treg stability and function, and protects them from the negative impact of IFNg. Despite these seminal advances and their translation into the clinic, there is a substantive sense that many aspects of Treg function, stability, control and fate in the TME remain unknown. In the next seven years, my program will focus on two major questions: (1) Are there other cytokines or suppressive mechanisms used by Tregs in the TME? Discovery, mechanistic dissection and translation of novel Treg-derived cytokines within the TME, with emphasis on novel EBI3-containing heterodimers. (2) Are there other mechanisms that impact Treg stability, function & survival in the TME? Identification and dissection of novel mechanisms that control Treg stability and function in the TME, and/or impact their capacity to modulate cell types in the TME. This program will have a significant impact on our understanding of how Tregs manipulate and control the TME, will provide novel targets and modalities for therapeutic intervention in cancer, and will hopefully inspire others to develop novel approaches to target Tregs in cancer and other diseases.