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. 2019 Sep 25;10(1):4346.
doi: 10.1038/s41467-019-12361-9.

Metabolomic Adaptations and Correlates of Survival to Immune Checkpoint Blockade

Affiliations
Free PMC article

Metabolomic Adaptations and Correlates of Survival to Immune Checkpoint Blockade

Haoxin Li et al. Nat Commun. .
Free PMC article

Abstract

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.

Conflict of interest statement

C.J., C.H. and M.W. are employees of Bristol-Myers Squibb. G.J.F. has patents/pending royalties on the PD-1 pathway from Roche, Merck, Bristol Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Dako, and Novartis and has served on advisory boards for CoStim, Novartis, Roche, Eli Lilly, Bristol-Myers-Squibb, Seattle Genetics, Bethyl Laboratories, Xios, and Quiet. F.S.H. receives consulting fees from Bristol Myers-Squibb, Merck, EMD-Serono, Novartis, Celldex, Amgen, Genentech/Roche, Incyte, Bayer, Partners Therapeutics, Sanofi, Pfizer and is on the advisory board for Apricity, Aduro, Pionyr, 7 Hills Pharma, Verastem, Compass Therapeutics, Takeda and holds equity and is on the advisory board for Torque. L.A.G. was a paid consultant for Novartis, Foundation Medicine, and Boehringer-Ingelheim; he held equity in Foundation Medicine and was a recipient of a grant from Novartis. L.A.G. is an employee of Roche. M.G. receives research funding from Bristol Myers-Squibb and Merck. T.K.C. receives research funds from AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Takeda. T.K.C. receives honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics. T.K.C has consulting or advisory role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group. T.K.C. does not serve within a speaker’s bureau. T.K.C. does not have leadership or employment in for-profit companies. Other present or past leadership roles of T.K.C. include Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney cancer Association Medical and Scientific Steering Committee). H.L., T.K.C. and M.G. have pending patents for biomarkers of immune checkpoint blockers. T.K.C. has stock ownership in Pionyr and Tempest. For T.K.C., travel, accommodations, and expenses, in relation to consulting, advisory roles, honoraria, medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic of study design and serum specimen collection. This study consisted of serum specimens from two phase 1 trials and one randomized phase 3 trial. The cancer and treatment type/dosing, number of serum samples collected at each time point, and number of metabolites identified by LC-MS are labeled as above. 63 overlapping metabolites were profiled in all three cohorts
Fig. 2
Fig. 2
Comprehensive serum metabolomic profiling reveals significantly up-regulated kynurenine in response to nivolumab treatment. a Volcano plots showing average serum metabolite (n = 106, represented as points) level changes after 4 weeks of nivolumab treatment compared to baseline in CA209-038 melanoma patients. b Histogram showing the changes of kynurenine/tryptophan (Kyn/Trp) ratios 4 weeks after nivolumab treatment compared to baseline in melanoma patients. c Volcano plot showing average serum metabolite (n = 106) changes between week 6 and week 4 after nivolumab treatment in melanoma patients. d Volcano plots showing average serum metabolite (n = 202) level changes after 4 weeks of nivolumab treatment compared to baseline in CheckMate 025 RCC patients. e Histogram showing the changes of Kyn/Trp ratios 4 weeks after nivolumab treatment compared to baseline in CheckMate 025 RCC patients. f Volcano plot showing average serum metabolite (n = 202) level changes after 4 weeks of everolimus treatment compared to baseline in CheckMate 025 RCC patients. g Pearson correlation analysis between Kyn/Trp ratios and PD-L1/IDO1/TDO mRNA expression at week 4, prior anti-CTLA4 treatment (ipilimumab), and tumor mutation load in melanoma patients. The q values in a, c, d, f were calculated based on paired t-tests for all profiled metabolites with Benjamini-Hochberg multiple testing corrections
Fig. 3
Fig. 3
Kyn/Trp ratio alterations associate with patient overall survival in two independent cohorts. a, b Volcano plots showing associations between fold changes (log2 scale) of different serum metabolites (n = 106) and overall survival in melanoma patients. The effect sizes refer to the regression coefficients in a Cox proportional hazards model and the points represent different metabolites. a 4 weeks after nivolumab treatment versus baseline, b 6 weeks after nivolumab treatment versus baseline. q values were calculated using Benjamini-Hochberg multiple testing corrections. A cutoff at q = 0.05 is shown as a horizontal line. c Table summarizing the hazard ratios (HR) of Kyn/Trp (log2 scale) as a predictor at different time points in relation to melanoma patient overall survival using a Cox proportional hazards model. CI, confidence interval. d Kaplan–Meier plot comparing the overall survival in melanoma patients with >50% increases in Kyn/Trp ratios versus those with decreases. e, Table summarizing the hazard ratios (HR) of Kyn/Trp (log2 scale) as a predictor at different time points in relation to CheckMate 025 RCC patient overall survival using a Cox proportional hazards model. f Kaplan–Meier plot comparing the overall survival in RCC patients with >50% increases in Kyn/Trp ratios versus those with decreases. The p values in d, f were based on log-rank tests

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