PD-1 and Tim-3 regulate the expansion of vaccine-induced tumor antigen-specific CD8+ T cells in patients with advanced melanoma (VAC3P.944)

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Abstract Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we have evaluated vaccine-induced CD8+ T cells for frequency, function and expression of the inhibitory receptors PD-1 and Tim-3 in patients with metastatic melanoma immunized with incomplete Freund’s adjuvant, CpG-oligodeoxynucleotide, and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V either alone, or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 whereas a minority also upregulated Tim-3 and the levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration inversely correlated with their expansion in vivo. PD-1 and Tim-3 blockades further enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades in addition to cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.