Effects of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation and resistance to tumor relapse

Abstract

Abstract Clinical studies have shown that αPD-1 therapy mediates a greater response rate compared to αCTLA-4 according to RECIST criteria. However, it may not be as durable as αCTLA-4. 25% of patients who initially responded to αPD-1 have tumor relapse within 24 months. In contrast, the 10-year survival rate of patients treated with αCTLA-4 is at least ~25% suggesting a durable response. The goal of this study is to understand the relationship between memory T-cell formation in tumor models mediated by checkpoint antibodies and tumor relapse. Our results have shown that αCTLA-4 could induce a superior memory antitumor response during tumor rechallenge on mice compared to that treated with αPD-1 after 80 days. We also showed that this memory antitumor response was antigen-specific. These antigen-specific memory T-cells in mice that were treated with αCTLA-4 had better proliferative potential with cytokine producing function and more CD62L+CD44+ memory T-cells were converted back to CD62L-CD44+ effectors during rechallenge. We found that αCTLA-4 and αPD-1 facilitated the development of CD4 and CD8 memory T-cells respectively. We also demonstrated that the memory antitumor activity mediated by the combination of αCTLA-4 and αPD-1 overlapped with αCTLA-4 alone suggesting the effect of the combined treatment is dominated by αCTLA-4.