Abstract 592: Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade

Abstract

Abstract Checkpoint blockade is able to achieve durable responses in a subset of patients, however the biological variables that distinguish responders from non-responders are not well understood. Furthermore, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. Given that PD-1 and CTLA-4 attenuate T cell activity through distinct mechanisms that are separated spatially and temporally, we hypothesized that responses to anti-CTLA-4 and anti-PD-1 are driven by distinct mechanisms. To address this hypothesis we utilized mass cytometry to comprehensively profile the effect of checkpoint blockade on tumor immune infiltrates in murine tumor models. This approach allows for the interrogation of greater than 40 analytes at single cell resolution. We demonstrate that high dimensional mass cytometry analysis enables unsupervised identification of biologically relevant tumor infiltrating immune populations with high sensitivity and specificity. Using this approach we analyzed immune infiltrates of MC38 and B16BL6 murine tumors in mice treated with anti-CTLA-4, anti-PD-1, or control antibodies. In both tumor models we identify 15 distinct T cell populations with 0.5% or greater frequency. The T cell populations identified in MC38 and B16BL6 tumors were highly congruent. Notably, some but not all of these T cell populations were responsive to checkpoint blockade. A subset of tumor infiltrating CD8 T cell populations expanded following both anti-CTLA-4 and anti-PD-1. Conversely, a subset of regulatory T cell populations contracted following both anti-CTLA-4 and anti-PD-1. Interestingly, we observed expansion of a Th1-like CD4 effector T cell population only in response to anti-CTLA-4 treatment. Thus, we find that anti-PD-1 predominantly engages subsets of tumor infiltrating CD8 T cells whereas anti-CTLA-4 engages both the CD4 and CD8 effector compartments. Our findings indicate that anti-CTLA-4 and anti-PD-1 utilize distinct cellular mechanisms to induce tumor rejection. These findings highlight the importance of expanding our mechanistic understanding of immunotherapeutic approaches for the rational design of combinatorial therapeutic approaches. Furthermore, these results demonstrate that mass cytometry analysis can be utilized to identify biologically relevant tumor infiltrating T cell populations. We acknowledge the MDACC core facility NCI Support Grant P30CA16672. Citation Format: Spencer C. Wei, Jacob H. Levine, Dana Pe'er, James P. Allison. Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2017-592