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

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; Tim F. Greten; Jennifer C. Jones; Cecilia Monge; Sandra Demaria; Silvia Formenti; Lorenzo Belluomini; Valeria Dionisi; Christophe Massard; Pierre Blanchard; Charlotte Robert; Clément Quevrin; Eloise Lopes; Céline Clémenson; Michele Mondini; Lydia Meziani; Yizhou Zhan; Chengbing Zeng; Qingxin Cai; Daphne Morel; Roger Sun; Pierre Antoine Laurent; Monica Mangoni; Vanessa Di Cataldo; Chiara Arilli; Maike Trommer; Simone Wegen; Sebastian Neppl; Rachel P. Riechelmann; Marcos P. Camandaroba; Elson Santos Neto; Pierre Edouard Fournier; Nicola Segata; Peter Holicek; Lorenzo Galluzzi; Aitziber Buqué; Carolina Alves Costa Silva; Lisa Derosa; Guido Kroemer; Chuangzhen Chen; Laurence Zitvogel; Eric Deutsch

doi:10.1016/j.ccell.2025.02.010

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

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

Tim F. Greten, Jennifer C. Jones, Cecilia Monge, Sandra Demaria, Silvia Formenti, Lorenzo Belluomini, Valeria Dionisi, Christophe Massard, Pierre Blanchard, Charlotte Robert, Clément Quevrin, Eloise Lopes, Céline Clémenson, Michele Mondini, Lydia Meziani, Yizhou Zhan, Chengbing Zeng, Qingxin Cai, Daphne Morel, Roger Sun, Pierre Antoine Laurent, Monica Mangoni, Vanessa Di Cataldo, Chiara Arilli, Maike Trommer, Simone Wegen, Sebastian Neppl, Rachel P. Riechelmann, Marcos P. Camandaroba, Elson Santos Neto, Pierre Edouard Fournier, Nicola Segata, Peter Holicek, Lorenzo Galluzzi, Aitziber Buqué, Carolina Alves Costa Silva, Lisa Derosa, Guido Kroemer, Chuangzhen Chen, Laurence Zitvogel, Eric Deutsch

Cancer Signaling and Microenvironment (CSM)

Université Paris-Sud
Université Paris-Saclay
Institut national de la santé et de la recherche médicale
Cancer Hospital of Shantou University Medical College
Heidelberg University
University of Trento
Gustave Roussy
Centre de Recherche des Cordeliers
Zhejiang Provincial People's Hospital
Zhejiang University
Technical University of Munich
National Institutes of Health
Cornell University
University of Verona
University of Florence
Azienda Ospedaliera Careggi
University of Cologne
Austin Health
Hospital A.C. Camargo
IHU Méditerranée Infection
IRCCS Istituto Europeo di Oncologia - Milano
Sotio Biotech
Assistance publique – Hôpitaux de Paris

Research output: Contribution to journal › Article › peer-review

57 Scopus 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⁺ 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.

Original language	English
Pages (from-to)	361-379.e10
Journal	Cancer Cell
Volume	43
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2025.02.010
State	Published - Mar 10 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

Keywords

bile acids
cancer
Christensenella minuta
dendritic cells
gut microbiota
metabolomics
radiotherapy
tumor immunosurveillance
Immune Checkpoint Inhibitors/pharmacology
Immunotherapy/methods
Humans
Middle Aged
Male
CD8-Positive T-Lymphocytes/immunology
Neoplasm Metastasis
B7-H1 Antigen/antagonists & inhibitors
Female
Retrospective Studies
Mice, Inbred C57BL
Gastrointestinal Microbiome
Intestines/pathology
Animals
Neoplasms/immunology
Mice
Aged

Access to Document

10.1016/j.ccell.2025.02.010

Cite this

Chen, J., Levy, A., Tian, A. L., Huang, X., Cai, G., Fidelle, M., Rauber, C., Ly, P., Pizzato, E., Sitterle, L., Piccinno, G., Liu, P., Durand, S., Mao, M., Zhao, L., Iebba, V., Felchle, H., Mallard de La Varende, A. L., Fischer, J. C., ... Deutsch, E. (2025). Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients. Cancer Cell, 43(3), 361-379.e10. https://doi.org/10.1016/j.ccell.2025.02.010

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

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.",

keywords = "bile acids, cancer, Christensenella minuta, dendritic cells, gut microbiota, metabolomics, radiotherapy, tumor immunosurveillance, Immune Checkpoint Inhibitors/pharmacology, Immunotherapy/methods, Humans, Middle Aged, Male, CD8-Positive T-Lymphocytes/immunology, Neoplasm Metastasis, B7-H1 Antigen/antagonists \& inhibitors, Female, Retrospective Studies, Mice, Inbred C57BL, Gastrointestinal Microbiome, Intestines/pathology, Animals, Neoplasms/immunology, Mice, Aged",

author = "Jianzhou Chen and Antonin Levy and Tian, \{Ai Ling\} and Xuehan Huang and Guoxin Cai and Marine Fidelle and Conrad Rauber and Pierre Ly and Eug{\'e}nie Pizzato and Lisa Sitterle and Gianmarco Piccinno and Peng Liu and Sylv{\`e}re Durand and Misha Mao and Liwei Zhao and Valerio Iebba and Hannah Felchle and \{Mallard de La Varende\}, \{Anne Laure\} and Fischer, \{Julius Clemens\} and Simon Thomas and Greten, \{Tim F.\} and Jones, \{Jennifer C.\} and Cecilia Monge and Sandra Demaria and Silvia Formenti and Lorenzo Belluomini and Valeria Dionisi and Christophe Massard and Pierre Blanchard and Charlotte Robert and Cl{\'e}ment Quevrin and Eloise Lopes and C{\'e}line Cl{\'e}menson and Michele Mondini and Lydia Meziani and Yizhou Zhan and Chengbing Zeng and Qingxin Cai and Daphne Morel and Roger Sun and Laurent, \{Pierre Antoine\} and Monica Mangoni and \{Di Cataldo\}, Vanessa and Chiara Arilli and Maike Trommer and Simone Wegen and Sebastian Neppl and Riechelmann, \{Rachel P.\} and Camandaroba, \{Marcos P.\} and Neto, \{Elson Santos\} and Fournier, \{Pierre Edouard\} and Nicola Segata and Peter Holicek and Lorenzo Galluzzi and Aitziber Buqu{\'e} and \{Alves Costa Silva\}, Carolina and Lisa Derosa and Guido Kroemer and Chuangzhen Chen and Laurence Zitvogel and Eric Deutsch",

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month = mar,

day = "10",

doi = "10.1016/j.ccell.2025.02.010",

language = "English",

volume = "43",

pages = "361--379.e10",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

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Chen, J, Levy, A, Tian, AL, Huang, X, Cai, G, Fidelle, M, Rauber, C, Ly, P, Pizzato, E, Sitterle, L, Piccinno, G, Liu, P, Durand, S, Mao, M, Zhao, L, Iebba, V, Felchle, H, Mallard de La Varende, AL, Fischer, JC, Thomas, S, Greten, TF, Jones, JC, Monge, C, Demaria, S, Formenti, S, Belluomini, L, Dionisi, V, Massard, C, Blanchard, P, Robert, C, Quevrin, C, Lopes, E, Clémenson, C, Mondini, M, Meziani, L, Zhan, Y, Zeng, C, Cai, Q, Morel, D, Sun, R, Laurent, PA, Mangoni, M, Di Cataldo, V, Arilli, C, Trommer, M, Wegen, S, Neppl, S, Riechelmann, RP, Camandaroba, MP, Neto, ES, Fournier, PE, Segata, N, Holicek, P, Galluzzi, L , Buqué, A, Alves Costa Silva, C, Derosa, L, Kroemer, G, Chen, C, Zitvogel, L & Deutsch, E 2025, 'Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients', Cancer Cell, vol. 43, no. 3, pp. 361-379.e10. https://doi.org/10.1016/j.ccell.2025.02.010

TY - JOUR

T1 - Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients

AU - Chen, Jianzhou

AU - Levy, Antonin

AU - Tian, Ai Ling

AU - Huang, Xuehan

AU - Cai, Guoxin

AU - Fidelle, Marine

AU - Rauber, Conrad

AU - Ly, Pierre

AU - Pizzato, Eugénie

AU - Sitterle, Lisa

AU - Piccinno, Gianmarco

AU - Liu, Peng

AU - Durand, Sylvère

AU - Mao, Misha

AU - Zhao, Liwei

AU - Iebba, Valerio

AU - Felchle, Hannah

AU - Mallard de La Varende, Anne Laure

AU - Fischer, Julius Clemens

AU - Thomas, Simon

AU - Greten, Tim F.

AU - Jones, Jennifer C.

AU - Monge, Cecilia

AU - Demaria, Sandra

AU - Formenti, Silvia

AU - Belluomini, Lorenzo

AU - Dionisi, Valeria

AU - Massard, Christophe

AU - Blanchard, Pierre

AU - Robert, Charlotte

AU - Quevrin, Clément

AU - Lopes, Eloise

AU - Clémenson, Céline

AU - Mondini, Michele

AU - Meziani, Lydia

AU - Zhan, Yizhou

AU - Zeng, Chengbing

AU - Cai, Qingxin

AU - Morel, Daphne

AU - Sun, Roger

AU - Laurent, Pierre Antoine

AU - Mangoni, Monica

AU - Di Cataldo, Vanessa

AU - Arilli, Chiara

AU - Trommer, Maike

AU - Wegen, Simone

AU - Neppl, Sebastian

AU - Riechelmann, Rachel P.

AU - Camandaroba, Marcos P.

AU - Neto, Elson Santos

AU - Fournier, Pierre Edouard

AU - Segata, Nicola

AU - Holicek, Peter

AU - Galluzzi, Lorenzo

AU - Buqué, Aitziber

AU - Alves Costa Silva, Carolina

AU - Derosa, Lisa

AU - Kroemer, Guido

AU - Chen, Chuangzhen

AU - Zitvogel, Laurence

AU - Deutsch, Eric

PY - 2025/3/10

Y1 - 2025/3/10

N2 - 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.

AB - 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.

KW - bile acids

KW - cancer

KW - Christensenella minuta

KW - dendritic cells

KW - gut microbiota

KW - metabolomics

KW - radiotherapy

KW - tumor immunosurveillance

KW - Immune Checkpoint Inhibitors/pharmacology

KW - Immunotherapy/methods

KW - Humans

KW - Middle Aged

KW - Male

KW - CD8-Positive T-Lymphocytes/immunology

KW - Neoplasm Metastasis

KW - B7-H1 Antigen/antagonists & inhibitors

KW - Female

KW - Retrospective Studies

KW - Mice, Inbred C57BL

KW - Gastrointestinal Microbiome

KW - Intestines/pathology

KW - Animals

KW - Neoplasms/immunology

KW - Mice

KW - Aged

UR - https://www.scopus.com/pages/publications/85219701577

U2 - 10.1016/j.ccell.2025.02.010

DO - 10.1016/j.ccell.2025.02.010

M3 - Article

C2 - 40068595

AN - SCOPUS:85219701577

SN - 1535-6108

VL - 43

SP - 361-379.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

UN SDGs

Keywords

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Institute Gustave-Roussy Details Findings in Metastatic Cancer (Low-dose Irradiation of the Gut Improves the Efficacy of Pd-l1 Blockade In Metastatic Cancer Patients)

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Press/Media

Institute Gustave-Roussy Details Findings in Metastatic Cancer (Low-dose Irradiation of the Gut Improves the Efficacy of Pd-l1 Blockade In Metastatic Cancer Patients)

Cite this