PD-1 blockade improves the anti-tumor potency of exhausted CD3+CD56+ NKT-like cells in patients with primary hepatocellular carcinoma

• Published in: Oncoimmunology Vol. 10; no. 1; p. 2002068
• Main Authors: Tao, Longxiang, Wang, Shanshan, Kang, Guijie, Jiang, Shanyue, Yin, Wenwei, Zong, Lu, Li, Jing, Wang, Xuefu
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: Carcinoma, Hepatocellular - drug therapy; CD8-Positive T-Lymphocytes; Hepatocellular carcinoma; Humans; immune exhaustion; immunotherapy; Liver Neoplasms - drug therapy; Natural Killer T-Cells; nkt-like cells; pd-1; Programmed Cell Death 1 Receptor; Hepatocellular carcinoma; immune exhaustion; pd-1; nkt-like cells; immunotherapy
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2021.2002068

CD3 + CD56 + NKT-like cells play pivotal roles in the anti-tumor immune defense response. However, little is known regarding circulating NKT-like cells in patients with primary hepatocellular carcinoma (HCC). In the present study, we demonstrate that circulating NKT-like cells in HCC patients are functionally impaired and anti-PD-1 blockade improves their anti-tumor potency. Circulating NKT cells were mainly comprised of CD8+ T cells. The frequencies and absolute counts of circulating NKT-like cells were comparable between HCC patents compared to healthy donors. NKT-like cells in HCC patients were impaired in their production of TNF-α and IFN-γ as well as cytotoxicity. The level of activating receptor NKG2D was significantly decreased on NKT-like cells in HCC patients. In contrast, the expression of inhibitory receptors PD-1, Tim-3, and CTLA-4 were markedly increased on NKT-like cells in HCC patients. Meanwhile, the expression of PD-L1 was also upregulated on NKT-like cells in HCC patients. In detail, PD-1 + NKT-like cells expressed lower levels of NKG2D, higher levels of Tim-3, and CTLA-4, and less IFN-γ when compared with PD-1 − NKT-like cells. Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy.