期刊
SIGNAL TRANSDUCTION AND TARGETED THERAPY
卷 6, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41392-020-00377-3
关键词
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资金
- National Key R&D Program of China [2017YFA0505803, 2018ZX10302205]
- National Natural Science Foundation of China [81730044, 91842308]
- Science and Information Technology of Guangzhou [201904020040]
- China Postdoctoral Science Foundation [2019M653190]
- Sun Yat-sen University Clinical Research 5010 Program Fund [2015024]
In this study, it was found that reshaping MDSCs through autocrine IFN-alpha/beta and TNF-alpha from activated T cells is crucial for successful anti-PD-1 treatment in colorectal cancer. This offers a novel strategy for improving the response and efficacy of anticancer therapy.
Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are shaped in response to anti-PD-1 treatment and what their impact on therapeutic efficacy is in colorectal cancer (CRC). In this study, the levels of infiltrating MDSCs were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment. A negative correlation between T-cell activation and MDSC function was also observed in fresh human CRC tissues. Mechanistic studies revealed that autocrine IFN-alpha/beta upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL-DR5 interaction and acted synergistically with TNF-alpha to inhibit MDSC function of suppressing the T-cell response through the JNK-NMDAR-ARG-1 pathway. Moreover, blockade of IFN-alpha/beta and TNF-alpha abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infiltrating MDSCs in a CRC mouse model. This result suggested that reprogramming MDSCs by IFN-alpha/beta and TNF-alpha from activated T cells was necessary for successful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy.
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