The upregulation of the inhibitory receptors BTLA and PD-1 defines a novel subset of dysfunctional tumor antigen-specific CD8+ T cells (127.19)

Abstract

Abstract Cytotoxic T cells present at the periphery or at tumor sites recognize tumor epitopes presented by melanoma cells but fail to induce tumor rejection in melanoma patients. Inhibitory receptors including PD-1 and Tim-3 expressed by spontaneous CD8+ T cells directed against the cancer-germline antigen NY-ESO-1 play a role in promoting tumor-induced T cell dysfunction. In the present study, we show that BTLA is upregulated on spontaneous NY-ESO-1-specific CD8+ T cells and that BTLA-expressing PD-1+Tim-3- CD8+ T cells represent the largest subset of NY-ESO-1-specific CD8+ T cells in melanoma patients. These cells were partially dysfunctional, producing less IFN-γ than BTLA- T cells, but more IFN-γ, TNF and IL-2 than the highly dysfunctional subset expressing all three receptors. Unlike PD-1, BTLA expression by NY-ESO-1-specific CD8+ T cells does not increase with higher T cell dysfunction or upon cognate antigen stimulation, suggesting that BTLA upregulation occurs independently of functional exhaustion driven by high antigen load. Finally, BTLA blockade adds to PD-1 and Tim-3 blockades, enhancing NY-ESO-1-specific CD8+ T cell expansion, proliferation and cytokine production. Collectively, our findings support the targeting of BTLA, PD-1 and Tim-3 pathways to reverse tumor-induced T cell dysfunction in patients with advanced melanoma.