Metabolic Imbalance Linked to Immune Checkpoint Blocker Resistance

A metabolic imbalance may explain some of the resistance to the immune checkpoint blocker nivolumab (Opdivo), according to the results of a new study led by scientists at the Dana-Farber Cancer Institute, Boston, the Broad Institute of Massachusetts Institute of Technology, and Harvard University.

The increasing production of the metabolite kynurenine out of the amino acid tryptophan in response to the nivolumab treatment may help identify the right patients for the immunotherapy, the scientists reported in Nature Communications. 

“Our findings further illustrate that checkpoint blockade in combination with IDO/TDO inhibitors might only benefit a selected group of patients with checkpoint-inhibition trigger kynurenine pathway activation,” wrote the authors. 

The “adaptive resistance mechanism” was studied in the metabolites within patient serum using liquid chromatography-mass spectrometry. 

The samples came from 3 immunotherapy trials: 2 phase I trials involving 78 patients with advanced melanoma and 91 patients with metastatic renal cell carcinoma (RCC); and the CheckMate 025 trial, a phase III investigation assessing 743 RCC patients.

The significant increases of the kynurenine/tryptophan ratio in the melanoma patients (at weeks 4 or 6, versus the baseline) “were consistently associated with greater risks for death,” (p = 1.2 × 10−4, hazard ratio [HR] = 2.71, 95% CI, 1.63–4.51; p = 2.5 × 10−4, HR = 2.26, 95% CI, 1.46–3.50, respectively), they wrote.

“For nivolumab-treated RCC patients, those with a >50% increases Kym/Trp had a median survival of 16.7 months while those with any Kyn/Trp deceases had a median survival of 31.3 months ((p = 4.3 × 10−4, log-rank test),” according to the paper. 

If suppressing the conversation pathway could be successfully accomplished, “tumor immune resistance could be reversed,” researchers wrote. 

“Our findings highlight the need and feasibility of patient stratification by monitoring serum Kyn/Trp alterations and more generally point to the relevance of metabolic adaptation in cancer immunotherapy,” they concluded. “Moreover, kynurenine production or kynurenine signaling may still be a relevant therapeutic target.”

Toni K. Choueiri, M.D., the co-senior author of the paper from the Dana-Farber Cancer Institute, said in a statement released at the time of the paper publication that metabolism may hold the key to changes in immune checkpoint blockade response. 

“One of the most important question in oncology is who responds and who doesn’t to modern PD-1 inhibitors,” said Choueiri. 

References:

Li H, Bullock K, Gurjao C, et al. Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nat Commun. 2019:10(4346)