Antibodies targeting the PD-1 pathway can reverse T cell exhaustion resulting in re-invigoration of immune responses. Anti-PD1 therapies such as pembrolizumab have been shown to be efficacious across a broad range of human cancers including melanoma with clinical responses correlating with immune changes in the tumor microenvironment. However, our understanding of the immune mechanism of anti-PD1 therapy in humans remains incomplete. Specifically, there is relatively little information about changes in the differentiation, activation and reversal of exhaustion in peripheral blood CD8 T cells and correlation with clinical outcome. We collected peripheral blood at serial time points before and after pembrolizumab therapy on 39 consecutive patients with Stage IV melanoma and analyzed changes in T cell subsets and differentiation using 16 parameter flow cytometry. Here we show that pembrolizumab treatment results in increases in the peripheral blood CD8/Treg ratio, as well as invigoration of CD8 T cells. Focusing on key CD8 T cell subsets expressing combinations of T-bet, Eomes, PD-1 and other inhibitory receptors has allowed greater focus on populations responding to re-invigoration by pembrolizumab treatment. This invigoration can be demonstrated by upregulation of granzyme B (GzmB) and Ki67 in key CD8 T cell subsets. An early increase in GzmB+Ki67+ cells translates into a later increase in GzmB+ cells suggesting an early wave of proliferation giving rise to a pool of re-invigorated CD8 T cells. T cell subsets that express markers of exhaustion including T-bet, Eomes, and inhibitory receptors may represent populations that are invigorated by anti-PD1 therapy. These changes may also correlate with clinical outcomes and therefore may be useful as a biomarker of response. These results show that T cell responses to pembrolizumab treatment can be tracked in an easily accessible peripheral blood compartment during therapy. The kinetics of immune response in key CD8 T cell subsets may inform us of optimal treatment duration as well as the nature and timing of cancer response to therapy.
Citation Format: Alexander Huang, Wei Xu, Shannon Harmon, Felix Quagliarello, Ramin Herati, Kristen Pauken, Bertram Bengsch, Lynn Schuchter, Ravi Amaravadi, Suzanne McGettigan, Tara Gangadhar, John Wherry. Anti-PD1 therapy and CD8 T cell invigoration in metastatic melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A036.
- ©2016 American Association for Cancer Research.