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

Authors
 Eun-Ah Bae  ;  Hyungseok Seo  ;  Byung-Seok Kim  ;  Jeongwon Choi  ;  Insu Jeon  ;  Kwang-Soo Shin  ;  Choong-Hyun Koh  ;  Boyeong Song  ;  Il-Kyu Kim  ;  Byung Soh Min  ;  Yoon Dae Han  ;  Sang Joon Shin  ;  Chang-Yuil Kang 
Citation
 Cancer Research, Vol.78(18) : 5315-5326, 2018 
Journal Title
 Cancer Research 
ISSN
 0008-5472 
Issue Date
2018
Abstract
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.Significance: These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. Cancer Res; 78(18); 5315-26. ©2018 AACR.
Full Text
http://cancerres.aacrjournals.org/content/78/18/5315.long
DOI
10.1158/0008-5472.CAN-18-0734
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
Yonsei Authors
민병소(Min, Byung Soh)
신상준(Shin, Sang Joon) ORCID logo https://orcid.org/0000-0001-5350-7241
한윤대(Han, Yoon Dae) ORCID logo https://orcid.org/0000-0002-2136-3578
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/165417
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