Abstract IA18: The mechanistic basis of cancer immunotherapy

Abstract

Abstract The advent of new approaches to the immunotherapy of cancer has caused a dramatic shift not only in the treatment of cancer but also in our understanding of cancer biology. The rapid rate of progress in the clinic, however, has outpaced our understanding of the basic mechanistic features that underlie the therapeutic advances. This is most notable in the case of “checkpoint” inhibitors, such as antibodies to the negative regulatory axis defined by PD-1 and PD-L1. While blocking the interaction of PD-L1 with PD-1 is often assumed to reverse the process of T-cell exhaustion, there is little direct evidence for this interpretation, an incomplete definition of what is meant by “exhaustion,” and a poor understanding of how PD-1 regulates T-cell activity. Starting with observations made in the clinic, we have used biochemical reconstitution together with in vivo analysis in mice to illuminate key features of the PD-L1/PD-1 axis, demonstrating that it functions primarily to regulate T-cell function by controlling signaling by costimulators such as CD28. Conditional knockout experiments also revealed that dendritic cell B7.1 plays a uniquely important role in activating CD28. Distinct from costimulatory molecules, entirely different regulatory mechanisms appear to regulate T-cell receptor signaling. Finally, we have begun to evaluate the origin of T cells that engage antitumor responses, results that further emphasize a need for continuous priming of antitumor T cells to maintain a potent anticancer response. Citation Format: Ira Mellman. The mechanistic basis of cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA18.