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

Cancer Research
Eun-Ah BaeChang-Yuil Kang

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 ...Continue Reading

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Citations

Aug 6, 2020·Nature Reviews. Cancer·Daniela BruniJérôme Galon
Mar 13, 2019·Archives of Pharmacal Research·Eun-Ah BaeChang-Yuil Kang
Aug 28, 2020·Frontiers in Immunology·Shin Foong Ngiow, Arabella Young
May 28, 2020·Frontiers in Immunology·Kevin O McNerneyHamid Bassiri
Aug 30, 2019·Nature Communications·Anna GalstyanJulia Y Ljubimova
Jun 4, 2021·Frontiers in Oncology·Guanyu YanMingjun Sun
Nov 18, 2021·Annual Review of Pathology·Laura MaiorinoMikala Egeblad

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