TY - JOUR TI - DGKA Mediates Resistance to PD-1 Blockade AU - Fu, Lingyi AU - Li, Sen AU - Xiao, WeiWei AU - Yu, Kuai AU - Li, Shuo AU - Yuan, Sujing AU - Shen, Jianfei AU - Dong, Xingjun AU - Fang, Ziqian AU - Zhang, Jianeng AU - Chen, Siyu AU - Li, Wende AU - You, Hua AU - Xia, Xiaojun AU - Kang, Tiebang AU - Tan, Jing AU - Chen, Gong AU - Yang, An-Kui AU - Gao, YuanHong AU - Zhou, Penghui T2 - Cancer Immunology Research AB - 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 signal pathways have been shown 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. Pharmacological 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. DA - 2021/01/01/ PY - 2021 DO - 10.1158/2326-6066.CIR-20-0216 DP - cancerimmunolres.aacrjournals.org J2 - Cancer Immunol Res LA - en SN - 2326-6066, 2326-6074 UR - https://cancerimmunolres.aacrjournals.org/content/early/2021/02/19/2326-6066.CIR-20-0216 Y2 - 2021/02/24/00:46:57 ER -