Metabolomic adaptations and correlates of survival to immune checkpoint blockade

• Published in: Nature communications Vol. 10; no. 1; pp. 4346 - 6
• Main Authors: Li, Haoxin, Bullock, Kevin, Gurjao, Carino, Braun, David, Shukla, Sachet A., Bossé, Dominick, Lalani, Aly-Khan A., Gopal, Shuba, Jin, Chelsea, Horak, Christine, Wind-Rotolo, Megan, Signoretti, Sabina, McDermott, David F., Freeman, Gordon J., Van Allen, Eliezer M., Schreiber, Stuart L., Stephen Hodi, F., Sellers, William R., Garraway, Levi A., Clish, Clary B., Choueiri, Toni K., Giannakis, Marios
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 140/58; 692/4028; 692/53; Adaptation; Adaptation, Physiological - drug effects; Aged; Antibodies; Antineoplastic Agents - therapeutic use; Apoptosis; Cancer; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Cell death; Clinical trials; Clinical Trials as Topic; Everolimus - therapeutic use; Female; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunotherapy; Inhibitors; Kaplan-Meier Estimate; Kidney cancer; Kidney Neoplasms - blood; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kynurenine - blood; Male; Melanoma; Melanoma - blood; Melanoma - drug therapy; Melanoma - metabolism; Metabolism; Metabolites; Metabolomics; Middle Aged; Monoclonal antibodies; multidisciplinary; Nivolumab - therapeutic use; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Renal cell carcinoma; Science; Science (multidisciplinary); Survival; Targeted cancer therapy; Treatment Outcome; Tryptophan; Tryptophan - blood; Tryptophan 2,3-dioxygenase
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12361-9

Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors. Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.