Upregulation of PD‐1 expression on tumor antigen‐specific CD8+ T cells in patients with advanced melanoma is associated with reversible immune dysfunction

The inhibitory receptor programmed death 1 (PD‐1) is a negative regulator of activated T cells and is upregulated on the surface of exhausted virus‐specific CD8+ T cells in chronically infected mice and humans. Blockade of this pathway using antibodies against PD ligand 1 (PD‐L1) reversed CD8+ T cell dysfunction. Here, we have investigated the role of the PD‐1/PD‐L1 pathway in impairing human tumor‐induced CD8+ T cells directed against multiple tumor antigens. In sharp contrast to the Epstein Barr virus (EBV) and influenza matrix (flu), we observed that ex vivo detectable CD8+ T cells recognizing well‐defined MHC class I‐restricted tumor epitopes in patients with advanced melanoma, upregulated PD‐1. After blockade of the PD1/PD‐L1 pathway, these tumor antigen‐specific CD8+ T cells exhibited increased proliferation and production of cytokines in response to the cognate antigen. Our findings contribute to a better understanding of the intriguing coexistence of strong tumor antigen‐specific CD8+ T cell responses with clinical progression in patients with advanced melanoma. They further provide a strong rationale for the use of PD 1/PDL‐1 blockade alone or in the context of cancer vaccines to reverse CD8+ T cell dysfunction and increase the likelihood of tumor regression. This work was supported by NIH/NCI Grants CA90360 and CA112198 (to HMZ)