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

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<sup>+</sup> 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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Publication Details

Journal
Cancer Cell
Published
2025-03-01
DOI
https://doi.org/10.1016/j.ccell.2025.02.010
Citations
33
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
34.50

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article

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

Marine Fidelle, Aitziber Buqué, Eugénie Pizzato, C. Arilli et al.
33 citations
Cancer Cell
Cancer Immunotherapy and Biomarkers
34.50
article

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

Marine Fidelle, Aitziber Buqué, Eugénie Pizzato, C. Arilli, Gianmarco Piccinno, Hannah Felchle, Antonin Lévy, Eric C Deutsch, Silvia C. Formenti, Peter Holíček, Lydia Meziani, Chuangzhen Chen, Pierre‐Yves Blanchard, Maike Trommer, Misha Mao, Marcos Pedro Guedes Camandaroba, Céline Clémenson, Pierre‐Edouard Fournier, Carolina Alves Costa Silva, Cecilia Monge, Clément Quevrin, Pierre-Antoine Laurent, Monica Mangoni, Sandra Demaria, Conrad Rauber, Lisa Derosa, Ai-Ling Tian, Sebastian Neppl, Simone Wegen, Charlotte Robert, Tim F. Greten, Vanessa Di Cataldo, Rachel P. Riechelmann, Pierre Ly, Nicola Segata, Valerio Iebba, Julius Fischer, Lorenzo Galluzzi, Yizhou Zhan, Chengbing Zeng, Valeria Dionisi, Laurence Zitvogel, Guido Kroemer, Lorenzo Belluomini, Qingxin Cai, Daphné Morel, Jennifer Jones, Jianzhou Chen, Christophe Massard, Sylvère Durand, Anne-Laure Mallard de La Varende, Lisa Sitterlé, Liwei Zhao, Peng Liu, Roger Sun, Elson Santos Neto, Xuehan Huang, Simon Thomas, Eloise Lopes, Guoxin Cai, Michele Mondini
article en
33 citations

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<sup>+</sup> 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.

Cancer CellVol. 43(3)
Délégation Paris 5 (FR), University of Verona (IT), Fox Chase Cancer Center (US), National Institutes of Health (US), Inserm (FR), University of Cologne (DE), University of Trento (IT), Université Paris Cité (FR), Cornell University (US), Heidelberg University (DE), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), University Hospital Heidelberg (DE), TUM Klinikum (DE), AC Camargo Hospital (BR), Shantou University (CN), Sorbonne Université (FR), Méditerranée Infection Foundation (FR), Cancer Hospital of Shantou University Medical College (CN), Centre de Recherche des Cordeliers (FR), La Ligue Contre le Cancer (FR), Assistance Publique – Hôpitaux de Paris (FR), Zhejiang Cancer Hospital (CN), Hôpital Européen Georges-Pompidou (FR), Hôpital Européen (FR), Sotio (Czechia) (CZ), Azienda Ospedaliero-Universitaria Careggi (IT), Zhejiang Provincial People's Hospital (CN), National Cancer Institute (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Cologne (DE), Olivia Newton-John Cancer Wellness & Research Centre (AU), Austin Health (AU), Hangzhou Medical College (CN), Weill Cornell Medicine (US), University of Florence (IT), European Institute of Oncology (IT), Technical University of Munich (DE), Zhejiang University (CN)
Amgen, AstraZeneca, Sanofi, F. Hoffmann-La Roche, Shantou University, Innovative Research Group Project of the National Natural Science Foundation of China, Seerave Foundation, Equipex, BeiGene, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Università degli Studi di Trento, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Université de Bourgogne, Astellas Pharma, Deutsche Krebshilfe, Institut National Du Cancer, European Society for Medical Oncology, Friedrich Naumann Stiftung, Universität zu Köln, Institut Gustave-Roussy, Direction Générale de l’offre de Soins, Shantou University Medical College, PharmaMar, Ono Pharmaceutical, Université de Paris, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, National Institutes of Health, Genentech, EMD Serono, Labex Immuno-Oncology, National Cancer Institute, MSDAVENIR, CHIST-ERA
Good health and well-being
Openalex Percentile: Top 0%
Cancer Immunotherapy and Biomarkers
34.50
DOIOpen Access PDFOpenAlex
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