Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling
(1) Suissa D (2) Fidelle M (3) Reich E (4) Pham TN (5) Thomas S (6) Bjrk JR (7) Liu P (8) Zhao L (9) Kitaoka K (10) Piard E (11) Lebhar I (12) Tian AL (13) Thelemaque C (14) Alves Costa Silva C (15) Deutsch E (16) Loriot Y (17) Segata N (18) Piccinno G (19) Hospers GAP (20) Maleki Vareki S (21) Silverman MS (22) Lenehan JG (23) Bataille V (24) Boulate D (25) Kuznetsova T (26) Weersma RK (27) Messaoudene M (28) Durand S (29) van der Aalst CM (30) de Koning HJ (31) Schuler-Thurner B (32) de Vries IJM (33) Rafie E (34) Saliby RM (35) Machaalani M (36) Haferkamp S (37) Schilling B (38) Porcari S (39) Ciccarese C (40) Iacovelli R (41) Cremolini C (42) Choueiri TK (43) Elkrief A (44) Kroemer G (45) Heinzerling L (46) Chamoto K (47) Ianiro G (48) Routy B (49) Derosa L (50) Paragios N (51) Zitvogel L
Suissa and Fidelle et al. performed targeted metabolomics to 4,336 plasma samples from 1,714 ICI-treated patients across 16 cohorts and trained an ML model that predicted 12‑month PFS, with histidine as a favorable marker and long-chain fatty acids and succinate associated with poor outcome. Histidine supplementation promoted mitochondrial FAO and regulated T cell exhaustion, enhancing ICI-induced antitumor immunity in fibrosarcoma and melanoma models. Histidine-rich diet was associated with favorable PFS in patients without dysbiosis-associated histidine catabolism, and fecal histidine levels inversely correlated with severe irAEs.
Contributed by Shishir Pant
(1) Suissa D (2) Fidelle M (3) Reich E (4) Pham TN (5) Thomas S (6) Bjrk JR (7) Liu P (8) Zhao L (9) Kitaoka K (10) Piard E (11) Lebhar I (12) Tian AL (13) Thelemaque C (14) Alves Costa Silva C (15) Deutsch E (16) Loriot Y (17) Segata N (18) Piccinno G (19) Hospers GAP (20) Maleki Vareki S (21) Silverman MS (22) Lenehan JG (23) Bataille V (24) Boulate D (25) Kuznetsova T (26) Weersma RK (27) Messaoudene M (28) Durand S (29) van der Aalst CM (30) de Koning HJ (31) Schuler-Thurner B (32) de Vries IJM (33) Rafie E (34) Saliby RM (35) Machaalani M (36) Haferkamp S (37) Schilling B (38) Porcari S (39) Ciccarese C (40) Iacovelli R (41) Cremolini C (42) Choueiri TK (43) Elkrief A (44) Kroemer G (45) Heinzerling L (46) Chamoto K (47) Ianiro G (48) Routy B (49) Derosa L (50) Paragios N (51) Zitvogel L
Suissa and Fidelle et al. performed targeted metabolomics to 4,336 plasma samples from 1,714 ICI-treated patients across 16 cohorts and trained an ML model that predicted 12‑month PFS, with histidine as a favorable marker and long-chain fatty acids and succinate associated with poor outcome. Histidine supplementation promoted mitochondrial FAO and regulated T cell exhaustion, enhancing ICI-induced antitumor immunity in fibrosarcoma and melanoma models. Histidine-rich diet was associated with favorable PFS in patients without dysbiosis-associated histidine catabolism, and fecal histidine levels inversely correlated with severe irAEs.
Contributed by Shishir Pant
ABSTRACT: Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.
Author Info:
(1) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (2) Universit Paris-Saclay,
Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (3) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (4) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (5) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (6) Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. (7) INSERM U1138 - Metabolism, Cancer & Immunity, quipe Labellise par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Universit Paris Cit, Sorbonne Universit, Paris, France. Universit Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. (8) INSERM U1138 - Metabolism, Cancer & Immunity, quipe Labellise par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Universit Paris Cit, Sorbonne Universit, Paris, France. Universit Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. (9) Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto, Japan. (10) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (11) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (12) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (13) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (14) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. Oncoclinicas&Co - Medica Scientia Innovation Research (MEDSIR), Sao Paulo, Brazil. Gonalo Moniz Institute, Fiocruz, Salvador, Brazil. Federal University of Bahia, Salvador, Brazil. (15) Department of Radiation Oncology, Gustave Roussy, Universit Paris-Saclay, INSERM U1355, RHU LySAIRI, Villejuif, France. (16) Department of Therapeutic Innovation and Early Trials (DITEP), INSERM U981, Gustave Roussy, Villejuif, France. (17) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (18) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (19) Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. (20) Verspeeten Family Cancer Centre, London Health Sciences Research Institute, London, Ontario, Canada. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Department of Oncology, Division of Experimental Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada. (21) Lawson Health Research Institute, London, Ontario, Canada. Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St Joseph's Health Care, London, Ontario, Canada. (22) Verspeeten Family Cancer Centre, London Health Sciences Research Institute, London, Ontario, Canada. Department of Oncology, Western University, London, Ontario, Canada. (23) Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. Department of Dermatology, Mount Vernon Cancer Centre, Northwood, UK. Department of Dermatology, Hemel Hempstead Hospital, West Hertfordshire NHS Trust, Hemel Hempstead, UK. (24) Department of Thoracic Surgery, Hpital-Nord-APHM, Aix-Marseille University, Marseille, France. Hpital Marie Lannelongue, GHPSJ, Le Plessis-Robinson, France. (25) Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. (26) Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. (27) Centre de Recherche du Centre Hospitalier de l'Universit de Montral (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. (28) INSERM U1138 - Metabolism, Cancer & Immunity, quipe Labellise par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Universit Paris Cit, Sorbonne Universit, Paris, France. Universit Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. (29) Department of Public Health, Erasmus Medical Centre - University Medical Centre Rotterdam, Rotterdam, The Netherlands. (30) Department of Public Health, Erasmus Medical Centre - University Medical Centre Rotterdam, Rotterdam, The Netherlands. (31) Department of Dermatology, Friedrich-Alexander-Universitt Erlangen-Nrnberg (FAU), Universittsklinikum Erlangen, Erlangen, Germany. Bavarian Cancer Research Center (BZKF), Erlangen, Germany. (32) Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands. (33) Centre de Recherche du Centre Hospitalier de l'Universit de Montral (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. Hemato-Oncology Division, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, Quebec, Canada. (34) Dana-Farber Cancer Institute, Boston, MA, USA. Yale School of Medicine, New Haven, CT, USA. (35) Dana-Farber Cancer Institute, Boston, MA, USA. (36) Bavarian Cancer Research Center (BZKF), Erlangen, Germany. Department of Dermatology, University Hospital Regensburg, Regensburg, Germany. (37) Department of Dermatology, Goethe University Frankfurt, University Hospital, Frankfurt am Main, Germany. (38) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore, Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (39) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore, Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (40) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore, Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (41) Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (42) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (43) Centre de Recherche du Centre Hospitalier de l'Universit de Montral (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. Hemato-Oncology Division, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, Quebec, Canada. (44) INSERM U1138 - Metabolism, Cancer & Immunity, quipe Labellise par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Universit Paris Cit, Sorbonne Universit, Paris, France. Universit Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. Institut du Cancer Paris CARPEM, Department of Biology, Hpital Europen Georges Pompidou, AP-HP, Paris, France. (45) Department of Dermatology, Friedrich-Alexander-Universitt Erlangen-Nrnberg (FAU), Universittsklinikum Erlangen, Erlangen, Germany. Bavarian Cancer Research Center (BZKF), Erlangen, Germany. Department of Dermatology and Allergy, LMU University Hospital LMU Munich, Munich, Germany. (46) Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto, Japan. Division of Cancer Immune Regulation, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto, Japan. (47) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore, Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (48) Centre de Recherche du Centre Hospitalier de l'Universit de Montral (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. Hemato-Oncology Division, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, Quebec, Canada. (49) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. Department of Medical Oncology, Gustave Roussy, Villejuif, France. (50) MICS Laboratory, CentraleSuplec, Universit Paris-Saclay, Gif-sur-Yvette, France. nikos.paragios@centralesupelec.fr. TheraPanacea, Paris, France. nikos.paragios@centralesupelec.fr. (51) Universit Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. Laurence.zitvogel@gustaveroussy.fr.
