Activation of NKT Cells in an Anti-PD-1-Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 18; pp. 5315 - 5326
• Main Authors: Bae, Eun-Ah, Seo, Hyungseok, Kim, Byung-Seok, Choi, Jeongwon, Jeon, Insu, Shin, Kwang-Soo, Koh, Choong-Hyun, Song, Boyeong, Kim, Il-Kyu, Min, Byung Soh, Han, Yoon Dae, Shin, Sang Joon, Kang, Chang-Yuil
• Format: Journal Article
• Language: English
• Published: United States 15.09.2018
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-0734

PD-1-based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1-resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1-resistant tumors by restoring the effector function of tumor antigen-specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1-resistant cancer. These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. .