Biology of PD-1 Checkpoint Blockade

Abstract The PD-1 pathway delivers inhibitory signals that function as a brake for immune responses and has wide-ranging immunoregulatory functions. Signals through the PD-1 pathway limit T cell activation and effector T cell responses. The PD-1 pathway also promotes T cell tolerance, inhibiting responses of self-reactive T cells. PD-L1 on non-hematopoietic cells can restrain T cell responses in tissue, thereby protecting tissues from immune-mediated damage and autoimmune attack. Tumors have exploited the pathway to establish an immunosuppressive microenvironment, and evade immune eradication. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers. Although PD-1 pathway inhibitors are revolutionizing cancer treatment, the mechanisms by which PD-1 regulates anti-tumor immunity are not fully understood. Further work is needed to understand mechanisms by which PD-1 pathway blockade induces anti-tumor immunity, and why PD-1 pathway blockade works or fails. This knowledge is needed to identify those who will benefit from PD-1 cancer immunotherapy and to develop rational combination therapies. This talk will discuss mechanisms by which PD-1 and its ligands control tumor immunity, including the relative contribution of tumor or host-derived PD-L1, and the impact of PD-1 modulation on metabolic fitness of T cells in the tumor microenvironment. Disclosures Sharpe: Merck: Patents & Royalties; Boehringer Ingelheim Gmbh: Patents & Royalties; Bristol Myers Squibb Company: Patents & Royalties; Bethyl Labs: Patents & Royalties; Medarex, Inc: Patents & Royalties; MedImmune, LLC: Patents & Royalties; Amplimmune, Inc.: Patents & Royalties; EMD Millipore: Patents & Royalties; Becton Dickinson and Co.: Patents & Royalties; BioXcell: Patents & Royalties; Cell Signaling Technology, Inc.: Patents & Royalties; Ventana Medical Systems, Inc.: Patents & Royalties; Exbio Antibody Diagnostics: Patents & Royalties; Biolegend: Patents & Royalties; eBioscience, Inc.: Patents & Royalties; Miltenyi Biotec, Inc.: Patents & Royalties; Life Sciences Advanced Technologies: Patents & Royalties; Novartis AG: Consultancy, Patents & Royalties, Research Funding; Genentech: Patents & Royalties; Roche: Patents & Royalties, Research Funding; SQZ Biotech: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc: Patents & Royalties; Genocea Biosciences: Consultancy; American Association of Immunologists: Membership on an entity's Board of Directors or advisory committees; National Institute of Allergy and Infectious Diseases: Membership on an entity's Board of Directors or advisory committees; American Association for Advancement of Science: Membership on an entity's Board of Directors or advisory committees; SU2C: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Quiet: Other: Spouse on SAB; UCB: Research Funding; Xios: Other: Spouse on SAB; Ipsen: Research Funding; Quark: Research Funding.