DGKA Mediates Resistance to PD-1 Blockade.

Lingyi Fu, Sen Li, WeiWei Xiao, Kuai Yu, Shuo Li, Sujing Yuan, Jianfei Shen, Xingjun Dong, Ziqian Fang, Jianeng Zhang, Siyu Chen, Wende Li, Hua You, Xiaojun Xia, Tiebang Kang, Jing Tan, Gong Chen, An-Kui Yang, YuanHong Gao, Penghui Zhou

Cancer immunology research 2021 Apr

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Immunologic checkpoint blockade has been proven effective in a variety of malignancies. However, high rates of resistance have substantially hindered its clinical use. Understanding the underlying mechanisms may lead to new strategies for improving therapeutic efficacy. Although a number of signaling pathways have been shown to be associated with tumor cell-mediated resistance to immunotherapy, T cell-intrinsic resistant mechanisms remain elusive. Here, we demonstrated that diacylglycerol kinase alpha (Dgka) mediated T-cell dysfunction during anti-PD-1 therapy by exacerbating the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade. Dgka inhibition also enhanced the efficacy of anti-PD-1 therapy. We further found that the expression of DGKA in cancer cells promoted tumor growth via the AKT signaling pathway, suggesting that DGKA might be a target in tumor cells as well. Together, these findings unveiled a molecular pathway mediating resistance to PD-1 blockade and provide a potential therapeutic strategy with combination immunotherapy. ©2021 American Association for Cancer Research.

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PMID: 33608256

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