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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 :
Bae EA
Seo H
Kim BS
Choi J
Jeon I
Shin KS
Koh CH
Song B
Kim IK
Min BS
Han YD
Shin SJ
Kang CY
Source :
Cancer research [Cancer Res] 2018 Sep 15; Vol. 78 (18), pp. 5315-5326. Date of Electronic Publication: 2018 Jul 16.
Publication Year :
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 .<br /> (©2018 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1538-7445
Volume :
78
Issue :
18
Database :
MEDLINE
Journal :
Cancer research
Publication Type :
Academic Journal
Accession number :
30012672
Full Text :
https://doi.org/10.1158/0008-5472.CAN-18-0734