Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
作者机构：State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouChina MOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat-sen UniversityGuangzhouChina First Afliated HospitalSun Yat-sen UniversityGuangzhouChina Department of Medical OncologyDana Farber Cancer InstituteBostonMA.USA
出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)
年 卷 期：2021年第6卷第2期
页 面：447-460页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：This work was supported by project grants from the National Key R&D Program of China(2017YFA0505803 and 2018ZX10302205) the National Natural Science Foundation of China(81730044 and 91842308) the Science and Information Technology of Guangzhou(201904020040) the China Postdoctoral Science Foundation(2019M653190) the Sun Yat-sen University Clinical Research 5010 Program Fund(2015024)
主 题：colorectal cancer programming
摘 要：Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor ***-derived suppressor cells(MDSCS)are key regulators of immunosuppressive networks and promote tumor ***,it remains unclear whether and how tumor-infltrating 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 infltrating 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 *** studies revealed that autocrine IFN-α/B upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL-DR5 interaction and acted synergistically with TNF-α to inhibit MDSC function of suppressing the T-cell response through the JNK NMDAR-ARG-1 ***,blockade of IFNa/βand TNF-α abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infltrating MDSCS in a CRC mouse *** result suggested that reprogramming MDSCS by IFN-α/βand TNF-α from activated T cells was necessary for succesful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy.
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