Citations

Abstract B7-H1 (aka PD-L1) blocking antibodies have been tested in the treatment of human cancers through blocking B7-H1 expressed by tumor cells; however, its impact on B7-H1 expressed by tumor-reactive CD8+ T cells is still unknown. Here, we report that tumor-reactive CD8+ T cells expressing B7-H1 were functional effector cells. An agonist antibody to PD-L1 deleted B7-H1+ PD-1+ tumor-reactive CD8+ T cells via activation of p38 MAPK, and failed to suppress tumor growth. As activation of p38 MAPK leads to CD8+ T cell apoptosis upon T cell activation, a PD-L1 antibody that activated p38 MAPK enhanced apoptosis of activated CD8+ T cells. An intracellular molecule, DNA-PKcs, was identified in association with B7-H1 and a DNA-PKcs inhibitor increased p38 MAPK activation in wild type but not in B7-H1 deficient CD8+ T cells. Our results suggest B7-H1 suppresses p38 MAPK activation via DNA-PKcs to prevent CD8+ T cell death. To maximize antitumor function, PD-L1 antibodies should be selected to avoid their collateral activation of p38 MAPK in tumor-reactive CD8+ T cells. Citation Format: Siyu Cao, Xin Liu, Xiaosheng Wu, Aaron Mansfield, Haidong Dong. B7-H1 identifies tumor-reactive effector CD8 T cells susceptible of deletion by agonist PD-L1 antibodies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A131.

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.