Abstract 5407: The upregulation of BTLA and PD-1 defines a novel subset of dysfunctional tumor antigen-specific CD8+ T cells

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+PD-1+Tim-3− CD8+ T cells represent the largest subset of NY-ESO-1-specific CD8+ T cells in melanoma patients. BTLA+PD-1+Tim-3− CD8+ T cells are partially dysfunctional, producing less IFN-γ than BTLA−PD-1+Tim-3− and BTLA−PD-1−Tim-3− but more IFN-γ, TNF and IL-2 than highly dysfunctional BTLA+PD-1+Tim-3+ NY-ESO-1-specific CD8+ T cells. 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 pathway 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. This work was supported by the National Institutes of Health/National Cancer Institute grants R01CA90360 and R01CA157467 (to H.M. Zarour), an award from the Melanoma Skin Spore grant NCI P50CA121973 (to H.M. Zarour) and a grant from the Cancer Research Institute (to H.M. Zarour). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5407. doi:1538-7445.AM2012-5407