Blocking either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death-1 (PD-1) pathway relieves the negative regulation of T-cells resulting in durable tumor rejection in patients with cancer and improved survival rate. However, it remains unclear how these immunotherapies affect memory T-cell response. Here we address whether anti-CTLA-4 and anti-PD-1 have different effects on memory T-cells. We used anti-CTLA-4 or anti-PD-1 therapy in combination with irradiated cancer vaccine in mice. After re-challenge, we observed that in murine tumor models, anti-CTLA-4 generates a more robust memory antitumor response than anti-PD-1 as demonstrated by smaller tumor volumes at all time points. We have traced and profiled antigen-specific CD8 T-cells throughout priming, memory phase, and re-challenge. We observed the memory responses generated by anti-CTLA-4 and anti-PD-1 diverge at priming; where anti-CTLA-4 generates more TCF-1+ memory-like T-cells than anti-PD-1, and remains apparent throughout activation and expansion as anti-PD-1 results in a higher percentage of TOX1+ terminally-differentiated T cells. During re-challenge, the memory T-cells generated by anti-CTLA-4 1) expand in greater frequency, 2) have greater cytokine production and antitumor activity, and 3) more frequently differentiate into the population of KLRG1+ effector CD8 T-cells than those generated with anti-PD-1. We found each of these traits correlated with a more effective memory response.

Citation Format: Stephen Mok, Nana-Ama A.S. Anang, James J. Mancuso, James P. Allison. Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4149.