Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8(+) exhausted-like T cells.
Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8(+) exhausted-like T cells.
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低剂量放射治疗联合PD-L1和VEGFA双重阻断可诱导肿瘤内活化的CD 8（+）耗竭样T细胞介导的肝癌抗肿瘤反应
DOI：
10.1038/s41467-023-43462-1
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发表时间：
2023-11-24
影响因子：
16.6
通讯作者：
Yang, Yang
中科院分区：
文献类型：
--
作者：
Li, Siqi;Li, Kun;Wang, Kang;Yu, Haoyuan;Wang, Xiangyang;Shi, Mengchen;Liang, Zhixing;Yang, Zhou;Hu, Yongwei;Li, Yang;Liu, Wei;Li, Hua;Cheng, Shuqun;Ye, Linsen;Yang, Yang
Atezolizumab（抗PD-L1）联合贝伐珠单抗（抗VEGFA）是晚期肝细胞癌（HCC）的一线免疫治疗，但从该方案中获益的患者数量仍然有限。在这里，我们将联合收割机双重PD-L1和VEGFA阻断（DPVB）与低剂量放疗（LDRT）相结合，后者可迅速使肿瘤发炎，使其易于接受免疫治疗。该组合疗法在各种临床前HCC模型中表现出由CD 8 + T细胞介导的上级抗肿瘤功效。治疗功效依赖于动员具有效应子功能和细胞溶解能力的耗竭样CD 8 + T细胞（CD 8 + Tex）。从机制上讲，LDRT通过从引流淋巴结（dLN）经由CXCL 10/CXCR 3轴募集干细胞样CD 8 + Tpex（祖细胞耗尽的CD 8 + T细胞）进入肿瘤而使肿瘤对DPVB敏感。总之，这些结果进一步支持LDRT与atezolizumab和贝伐珠单抗联合用药的原理及其临床转化。越来越多的临床前和临床研究已经调查了联合放射治疗和免疫治疗的抗肿瘤疗效。在本文中，作者报告了低剂量放疗增强了VEGFA和PD-L1双重阻断在肝细胞癌临床前模型中的抗肿瘤作用。
Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8+ T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8+ T cells (CD8+ Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8+ Tpex, the progenitor exhausted CD8+ T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation. An increasing number of preclinical and clinical studies have investigated the antitumor efficacy of combined radiotherapy and immunotherapy. Here the authors report that low-dose radiotherapy enhances the antitumor effect of dual VEGFA and PD-L1 blockade in preclinical models of hepatocellular carcinoma.
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影响因子：
50.3
作者：
Duraiswamy J;Turrini R;Minasyan A;Barras D;Crespo I;Grimm AJ;Casado J;Genolet R;Benedetti F;Wicky A;Ioannidou K;Castro W;Neal C;Moriot A;Renaud-Tissot S;Anstett V;Fahr N;Tanyi JL;Eiva MA;Jacobson CA;Montone KT;Westergaard MCW;Svane IM;Kandalaft LE;Delorenzi M;Sorger PK;Färkkilä A;Michielin O;Zoete V;Carmona SJ;Foukas PG;Powell DJ Jr;Rusakiewicz S;Doucey MA;Dangaj Laniti D;Coukos G
通讯作者：
Coukos G
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
25.7
作者：
Cheng, Ann-Lii;Qin, Shukui;Finn, Richard S.
通讯作者：
Finn, Richard S.
影响因子：
29.4
作者：
Chiu, David Kung-Chun;Yuen, Vincent Wai-Hin;Wong, Carmen Chak-Lui
通讯作者：
Wong, Carmen Chak-Lui
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii