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.
Highlights
Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits
Our study consisted of two Phase I trials (CA209038, NCT01621490; CA209-009, NCT01358721), which included 78 patients with advanced melanoma and 91 patients with metastatic renal cell carcinoma (RCC) treated with nivolumab[8,11]
We found that at baseline, higher Kyn/Trp ratios associated with shorter overall survival both for the nivolumab- and the everolimus-treated patients (p = 3.6 × 10−4, HR = 1.79, 95% CI, 1.30–2.47; p = 1.7 × 10−5, HR = 2.06, 95% CI, 1.48–2.85; Cox model) (Fig. 3e, Supplementary Fig. 3a, b)
Summary
Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. 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. To understand the mechanisms of response and resistance, recent studies have focused on neoantigens[5,6], copynumber alterations[7], and transcriptional signatures[8,9] of tumor tissues collected from patients treated with immune-checkpoint inhibitors. Our findings have implications for the design and interpretation of novel combination therapies involving checkpoint inhibition
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