Chen and Levy et al. showed that incidental intestinal low-dose irradiation (ILDR) at 0.25–3 Gy conferred survival benefits in patients with advanced cancers across eight retrospective cohorts, and in tumor-bearing mice receiving ICB or chemotherapy. Christensenellaceae species in the gut shifted metabolism from immunosuppressive anaerobic glycolysis to the production of immunostimulatory secondary bile acids (BAs) and indoles, promoted mregDC trafficking to TdLNs, and enhanced the anti-cancer efficacy of ILDR combined with PD-L1 blockade in CD8+ T cell-dependent manner. A phase 2 prospective trial supported the benefit of 1 Gy ILDR.
Contributed by Shishir Pant
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 (³1 and ²3 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.
Author Info: (1) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National
Author Info: (1) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France; Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China. (2) Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Department of Radiation Oncology, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (3) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (4) Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China. (5) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (6) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France; CICBT1428, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (7) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France; Department of Gastroenterology and Infectious Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany. (8) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (9) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (10) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (11) Department of Computational, Cellular and Integrative Biology, University of Trento, 38123 Trento, Italy. (12) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, quipe Labellise - Ligue Nationale contre le Cancer, Universit Paris Cit, Sorbonne Universit, 75006 Paris, France. (13) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France. (14) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, quipe Labellise - Ligue Nationale contre le Cancer, Universit Paris Cit, Sorbonne Universit, 75006 Paris, France; General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Zhejiang University, Hangzhou, Zhejiang 310000, China. (15) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, quipe Labellise - Ligue Nationale contre le Cancer, Universit Paris Cit, Sorbonne Universit, 75006 Paris, France. (16) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France. (17) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, quipe Labellise - Ligue Nationale contre le Cancer, Universit Paris Cit, Sorbonne Universit, 75006 Paris, France; Technical University of Munich (TUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Department of Radiation Oncology, 81675 Munich, Germany. (18) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (19) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, quipe Labellise - Ligue Nationale contre le Cancer, Universit Paris Cit, Sorbonne Universit, 75006 Paris, France; Technical University of Munich (TUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Department of Radiation Oncology, 81675 Munich, Germany. (20) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (21) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (22) Translational Nanobiology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (23) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (24) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA. (25) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA. (26) Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy. (27) Department of Radiation Oncology, University of Verona Hospital Trust, 37126 Verona, Italy. (28) Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France; Drug Development Department (DITEP), Gustave Roussy Cancer Campus, 94805 Villejuif, France. (29) Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (30) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (31) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (32) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (33) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (34) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (35) INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (36) Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China. (37) Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China. (38) Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China. (39) Department of Radiation Oncology, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (40) Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Department of Radiation Oncology, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (41) Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Department of Radiation Oncology, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (42) Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences"Mario Serio" University of Florence, 50134 Florence, Italy. (43) Radiation Oncology Unit, Azienda Ospedaliero Universitaria Careggi, 50134 Florence, Italy. (44) Medical Physics Unit, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy. (45) Department of Radiation Oncology, Cyberknife and Radiotherapy, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Olivia Newton-John Cancer Wellness & Research Centre, Austin Health, Department of Radiation Oncology, Heidelberg VIC 3084, Melbourne, Australia. (46) Department of Radiation Oncology, Cyberknife and Radiotherapy, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany. (47) Department of Radiation Oncology, Cyberknife and Radiotherapy, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany. (48) Department of Clinical Oncology, AC Camargo Cancer Center, So Paulo 01509-900, Brazil. (49) Department of Clinical Oncology, AC Camargo Cancer Center, So Paulo 01509-900, Brazil. (50) Department of Radiation Oncology, AC Camargo Cancer Center, So Paulo 01509-001, Brazil. (51) IHU Mditerrane Infection, 13005 Marseille, France. (52) Department of Computational, Cellular and Integrative Biology, University of Trento, 38123 Trento, Italy; IEO, Istituto Europeo di Oncologia IRCCS, 20139 Milan, Italy. (53) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Sotio Biotech, 19000 Prague, Czech Republic. (54) Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA. (55) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA. (56) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France. (57) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France; CICBT1428, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. (58) Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Cancer Campus, 94805 Villejuif, France; Centre de Recherche des Cordeliers, INSERM U1138, quipe Labellise - Ligue Nationale contre le Cancer, Universit Paris Cit, Sorbonne Universit, 75006 Paris, France; Institut du Cancer Paris CARPEM, Department of Biology, Hpital Europen Georges Pompidou, AP-HP, 75015 Paris, France. (59) Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China. Electronic address: czchen2@stu.edu.cn. (60) Gustave Roussy Cancer Campus (GRCC), Clinicobiome, 94805 Villejuif Cedex, France; Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Institut National de la Sant Et de la Recherche Mdicale (INSERM) UMR 1015, Equipe Labellise-Ligue Nationale contre le Cancer, 94805 Villejuif, France; CICBT1428, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France. Electronic address: Laurence.zitvogel@gustaveroussy.fr. (61) Facult de Mdecine, Universit Paris-Saclay, 94270 Kremlin-Bictre, France; Department of Radiation Oncology, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France; INSERM U1030, Radiothrapie Molculaire et Innovations Thrapeutiques, Gustave Roussy Cancer Campus (GRCC), 94805 Villejuif, France.
