免疫疗法
细胞毒性T细胞
NKG2D公司
效应器
癌症研究
免疫系统
获得性免疫系统
医学
先天免疫系统
肿瘤微环境
癌症免疫疗法
渗透(HVAC)
免疫
封锁
免疫学
T细胞
生物
放射治疗
CD8型
抗原呈递
免疫检查点
先天性淋巴细胞
作者
Fernanda G. Herrera,Catherine Ronet,Maria Ochoa de Olza,David Barras,Isaac Crespo,Massimo Andreatta,Jesus Corria-Osorio,Aodrenn Spill,Fabrizio Benedetti,Raphael Genolet,Angela Orcurto,Martina Imbimbo,Eleonora Ghisoni,Blanca Navarro Rodrigo,Dominik R. Berthold,Apostolos Sarivalasis,Khalil Zaman,Rafael Duran,Clarisse Dromain,John Prior
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-09-03
卷期号:12 (1): 108-133
被引量:429
标识
DOI:10.1158/2159-8290.cd-21-0003
摘要
Abstract Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell–infiltrated tumors. Significance: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors. This article is highlighted in the In This Issue feature, p. 1
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