Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients

IF 44.5 1区医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2025-03-10 DOI:10.1016/j.ccell.2025.02.010

Jianzhou Chen, Antonin Levy, Ai-Ling Tian, Xuehan Huang, Guoxin Cai, Marine Fidelle, Conrad Rauber, Pierre Ly, Eugénie Pizzato, Lisa Sitterle, Gianmarco Piccinno, Peng Liu, Sylvère Durand, Misha Mao, Liwei Zhao, Valerio Iebba, Hannah Felchle, Anne-Laure Mallard de La Varende, Julius Clemens Fischer, Simon Thomas, Eric Deutsch

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Abstract

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8⁺ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

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肠道低剂量照射可提高转移性癌症患者PD-L1阻断的疗效

控制局部放疗对癌症患者的体外效应的机制仍然是一个开放的难题。本研究表明，在8组癌症患者和荷瘤小鼠的回顾性队列中，脱靶肠道低剂量照射（ILDR）增加了免疫检查点抑制剂或化疗的临床益处。ILDR的体外效应取决于剂量（≥1 Gy和≤3 Gy）以及代谢和免疫宿主-微生物群在基线时的相互作用，允许CD8+ T细胞激活而不衰竭。不同的分钟克里斯滕森菌菌株选择性地增强了ILDR和PD-L1阻断的抗癌功效，使表达PD-L1的肠道树突状细胞迁移到肿瘤引流淋巴结。一项介入性2期研究提供了概念证明，ILDR可以规避癌症患者对一线或二线免疫治疗的耐药性。有必要进行前瞻性临床试验，以确定ILDR的最佳剂量和适应症，以最大限度地发挥其治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.