NKT cell ligand-induced cytokines enhance antitumor effects with PD-1 blockade by reinvigorating exhausted CD8 T cells.

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Abstract Various immune checkpoint blockades have shown great promise for cancer patients. Anti-PD-1 therapies are known to reinvigorate exhausted immune cells, which progressively have lost effector function after chronic exposure to antigen. Although anti-PD-1 blockades were tested in various clinical trials on a wide range of tumors, many have observed clinical efficacy in only a portion of the patients tested. As such, these anti-PD-1 resistance or non-responsiveness needs to be overcome by combination therapeutic approaches that can synergize with existing immune checkpoint blockades. In this study, we investigated the effects of cytokines induced by invariant Natural Killer T (iNKT) cell ligand stimulation, more specifically α-galactosylceramide (αGC), on exhausted CD8 T cells. We used a mouse tumor model expressing ovalbumin antigen (OVA) and tracked OVA-specific CD8 T cells to show the effects on exhausted CD8 T cells in the tumor. αGC-induced cytokines not only enhanced the effector functions, but also diversified the functionality of exhausted CD8 T cells in vitro. Also, administration of αGC-loaded antigen presenting cells (APCs) restored exhausted CD8 T cell functions and led to higher cytotoxic effects in vivo. Among αGC-induced cytokines, we found IL-2 and IL-12 to be crucial in enhancing exhausted CD8 T cell function in mouse tumors and patient tumors. Furthermore, we showed that αGC-loaded APCs bring synergistic effects with PD-1 blockade in a mouse therapeutic tumor model. Our studies suggest a new insight for applying αGC as an adjuvant in cancer immunotherapy.

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