Type I Interferon Promotes Antitumor T Cell Response in CRPC by Regulating MDSC.
Type I Interferon Promotes Antitumor T Cell Response in CRPC by Regulating MDSC.
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DOI：
10.3390/cancers13215574
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发表时间：
2021-11-08
期刊：
影响因子：
5.2
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Fan L;Xu G;Cao J;Li M;Zhang H;Li F;Qi X;Zhang X;Li Z;Han P;Yang X
尽管雄激素阻断治疗后最初肿瘤消退，但大多数患者最终会发生去势抵抗性前列腺癌（CRPC）复发。免疫治疗旨在激活宿主免疫系统对抗癌症，在各种实体肿瘤中取得了显著的治疗效果。本研究的目的是探讨CRPC发展过程中免疫反应的机制，并筛选有效的免疫治疗CRPC。我们发现干扰素-α（IFNα）可直接抑制CRPC的进展，减少免疫抑制性粒细胞髓源性抑制细胞（G-MDSCs）在肿瘤微环境（TME）中的聚集，并削弱G-MDSCs对T细胞活化的抑制功能。本研究为CRPC的临床治疗提供了一种潜在的策略。背景：转移性去势抵抗性前列腺癌（CRPC）是前列腺癌患者死亡的主要原因。在这里，我们的目的是确定参与CRPC发展的免疫调节机制，并确定针对CRPC的潜在免疫疗法。方法：采用Myc-CaP细胞建立去势后免疫功能正常的FVB小鼠CRPC模型。在CRPC发展过程中分析了肿瘤微环境（TME）的免疫细胞谱。在CRPC肿瘤模型中筛选不同的免疫疗法，并在体外和体内研究其功效和潜在机制。结果：在CRPC发生发展过程中，TME中粒细胞髓源性抑制细胞（G-MDSC）的比例增加。在测试的免疫疗法中，IFNα在减少Myc-CaP CRPC肿瘤生长方面比抗PD-L1、抗CTLA-4、抗4-1BB、IL-2和IL-9更有效。在CRPC小鼠中，IFNα在体外分化期间和体内都减少了G-MDSC的数量。IFNα可降低G-MDSC对T细胞增殖和活化的抑制作用。结论：G-MDSCs是CRPC有效免疫治疗的关键。IFNα治疗是一种有前景的CRPC治疗策略。除了直接抑制肿瘤生长和促进T细胞启动外，IFNα还减少G-MDSC的数量和抑制功能，并恢复T细胞活化。
Despite initial tumor regression following androgen blockade treatment, relapse of castration-resistant prostate cancer (CRPC) eventually occurs in most patients. Immunotherapy aims to activate the host immune system to fight against cancer and has achieved significant therapeutic effects in various solid tumors. The purpose of our research was to investigate the mechanisms underlying the immune response during CRPC development and to screen effective immunotherapies against CRPC. We found that interferon-α (IFNα) directly inhibited the progression of CRPC, reduced the accumulation of the immune suppressive granulocytic myeloid-derived suppressor cells (G-MDSCs) in the tumor microenvironment (TME), and impaired the inhibitory function of G-MDSCs on T cell activation. This research provides a potential strategy for the clinical treatment of CRPC. Background: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among prostate cancer patients. Here, our aim was to ascertain the immune regulatory mechanisms involved in CRPC development and identify potential immunotherapies against CRPC. Methods: A CRPC model was established using Myc-CaP cells in immune-competent FVB mice following castration. The immune cell profile of the tumor microenvironment (TME) was analyzed during CRPC development. Different immunotherapies were screened in the CRPC tumor model, and their efficacies and underlying mechanisms were investigated in vitro and in vivo. Results: During CRPC development, the proportion of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the TME increased. Among the immunotherapies tested, IFNα was more effective than anti-PD-L1, anti-CTLA-4, anti-4-1BB, IL-2, and IL-9 in reducing Myc-CaP CRPC tumor growth. IFNα reduced the number of G-MDSCs both in vitro during differentiation and in vivo in CRPC mice. Furthermore, IFNα reduced the suppressive function of G-MDSCs on T cell proliferation and activation. Conclusion: G-MDSCs are crucial to effective immunotherapy against CRPC. Treatment with IFNα presents a promising therapeutic strategy against CRPC. Besides the direct inhibition of tumor growth and the promotion of T cell priming, IFNα reduces the number and the suppressive function of G-MDSCs and restores T cell activation.
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影响因子：
11.5
作者：
Di Mitri, Diletta;Toso, Alberto;Alimonti, Andrea
通讯作者：
Alimonti, Andrea
影响因子：
158.5
作者：
Kantoff, Philip W.;Higano, Celestia S.;Young, J.
通讯作者：
Young, J.
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
32.4
作者：
Jego, G;Palucka, AK;Banchereau, J
通讯作者：
Banchereau, J
DOI：
10.1084/jem.20101158
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamond MS;Kinder M;Matsushita H;Mashayekhi M;Dunn GP;Archambault JM;Lee H;Arthur CD;White JM;Kalinke U;Murphy KM;Schreiber RD
通讯作者：
Schreiber RD