Déborah Suissa, Marine Fidelle, Ella Reich, Thao-Nguyen Pham, Simon Thomas, Johannes R. Björk, P N Liu, Liwei Zhao, Koji Kitaoka, Eléonore Piard, Isabelle Lebhar, Ai-Ling Tian, Cassandra Thélémaque, Carolina Alves Costa Silva, Éric Deutsch, Yohann Loriot, Nicola Segata, Gianmarco Piccinno, Geke A.P. Hospers, Saman Maleki Vareki, Michael S. Silverman, John Lenehan, Véronique Bataille, David Boulate, Tatiana Kuznetsova, Rinse K. Weersma, Meriem Messaoudene, Sylvère Durand, Carlijn M. van der Aalst, Harry J. de Koning, Beatrice Schuler-Thurner, I. Jolanda M. de Vries, Edmond Rafie, Renée Maria Saliby, Marc Machaalani, Sebastian Haferkamp, Bastian Schilling, Serena Porcari, Chiara CICCARESE, Roberto Iacovelli, Chiara Cremolini, Toni K. Choueiri, Arielle Elkrief, Guido Kroemer, Lucie Heinzerling, Kenji Chamoto, Gianluca Ianiro, Bertrand Routy, Lisa Derosa, Nikos Paragios, Laurence Zitvogel
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. Mass-spectrometry-based metabolomic analysis of plasma samples from multiple cohorts of patients treated with immunotherapy across five distinct tumor types, followed by machine learning enabled identification of metabolic signatures, as well as functional exploration, reveals association of increased plasma histidine levels with prolonged survival and its potential for therapeutic intervention.