Overcoming resistance to anti-PD1 immunotherapy

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ABSTRACT Novel immunotherapies for cancer are having a major clinical impact, in particular anti-PD-1 mAbs which have been FDA-approved for 20 cancer entities. However, the mechanisms that explain why a subset of patients fails to respond to these therapies is incompletely understood. Understanding these mechanisms should lead to new therapeutic strategies for expanding efficacy further. Our prior data indicated that a baseline T cell-inflamed tumor microenvironment was predictive of response to anti-PD-1, which augments the functionality of CD8+ T cells already present within the tumor microenvironment. During the previous funding period, we made multiple novel discoveries that have been paradigm-shifting for the field, which have coalesced to motivate continued investigation into 5 research directions: investigation of novel T cell immune checkpoints, innate immune strategies to promote de novo T cell responses in the tumor microenvironment, tumor cell-intrinsic oncogenic events mediating immune resistance, regulation of anti-tumor immunity by the commensal microbiota, and germline variants influencing host anti- tumor T cell responses. Each of these directions is identifying novel therapeutic opportunities that are expected to expand the circle of efficacy for checkpoint blockade immunotherapy in the clinic.