Bim identifies tumor-reactive effector CD8+ T cells in cancer patients respond to anti-PD-1 therapy

Abstract

Abstract Endogenous tumor-reactive CD8+ T cell responses to tumors are controlled by immune checkpoints. Immune checkpoint blockade strategy has demonstrated therapeutic effects in some solid cancers. However, only a portion of patients responds to this therapy and there are no biomarkers to help predict and monitor treatment outcomes. We report that Bim is a downstream signaling molecule of the PD-1 pathway that reflects the degree of PD-1 interaction with its ligand B7-H1. B7-H1 protein directly induced Bim protein up-regulation in pre-activated human CD8+ T cells via regulation of AKT activation and phosphorylation of Bim. In mouse models, genetic absence of PD-1 in T cells and B7-H1 deficiency in tumors prevented Bim up-regulation in tumor-infiltrating CD8+ T cells. Among tumor-reactive PD-1+ CD11ahigh CD8+ T cells in the peripheral blood of cancer patients, Bim expression was significantly associated with expression of PD-1 and effector cell markers (T-bet and granzyme B). The frequency of Bim+ PD-1+ CD8+ T cells significantly increased in the peripheral blood of advanced melanoma patients compared to healthy donors. In melanoma patients, high Bim levels were correlated with poor overall survival. Importantly, patients who experienced clinical benefit after anti-PD-1 therapy had higher frequency of Bim+PD-1+CD8+ T cells in the peripheral blood at baseline compared to non-responding patients; however, this cell population decreased significantly after successful anti-PD-1 therapy. Our results indicate that Bim reflects the degree of PD-1 interaction with its ligand PD-L1 in effector CD8+ T cells, and measurement of Bim levels may provide a less invasive method to monitor or predict responses to anti-PD-1 therapy.