期刊
CANCER IMMUNOLOGY RESEARCH
卷 9, 期 4, 页码 371-385出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0216
关键词
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资金
- National Key Research and Development Program of China [2016YFA0500304]
- National Natural Science Foundation in China [81773052, 81572806, 81802853]
- Guangzhou Science Technology and Innovation Commission [201607020038]
- Science and Technology Projects of Guangdong Province [2016A020215086]
- Guangdong Innovative and Entrepreneurial Research Team Program [2016ZT06S638]
- Medical Scientific Research Foundation of Guangdong Province [2016111214046444]
- leading talents of Guangdong Province program
The study demonstrated that Dgka mediates T-cell dysfunction during anti-PD-1 therapy. Inhibiting Dgka can delay T-cell exhaustion and enhance the efficacy of anti-PD-1 therapy. Additionally, the expression of DGKA in cancer cells promotes tumor growth via the AKT signaling pathway.
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.
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