Abstract 2981: Clonal deletion of tumor-specific T cells by combination checkpoint blockade compromises antitumor efficacy in low tumor burden states

A myriad of combination immunotherapies is being developed as cancer treatments with the goal of enhancing antitumor immunity. We found that depending on the disease setting, combined immune checkpoint blockade may not always lead to synergistic antitumor effects. While combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise antitumor immunity in the low tumor burden state in preclinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced apoptosis of tumor-specific T cells. These changes further alter the overall T-cell receptor repertoire. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. Deficiency of IFN-γ receptor on immune cells rescues this phenotype and restores antitumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their wild-type counterparts in tumor-bearing mice receiving combination therapy. Finally, combination therapy induces significantly higher levels of IFN-γ in the low versus high tumor burden state on a per cell basis, reflecting their less exhausted immune status. Thus, the optimal immunotherapy strategy may depend on disease context, and may not always favor more potent combination immunotherapies. Citation Format: Chien-Chun Steven Pai, Xiaoqing Lu, Donald Simons, Michel DuPage, Kole T. Roybal, Mingyi Chen, Serena Kwek, Amy-Jo Casbon, Gillian A. Kinsbury, Lawrence Fong. Clonal deletion of tumor-specific T cells by combination checkpoint blockade compromises antitumor efficacy in low tumor burden states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2981.