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Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Haoxin Li1,2,3, Kevin Bullock2, Carino Gurjao1,2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Nature Communications
|September 27, 2019
PubMed

Insights

Immune checkpoint inhibitors show promise, but many cancer patients lack lasting benefits. This study found increased kynurenine/tryptophan ratios in patients treated with PD1 blockade, indicating resistance and poorer survival outcomes.

Area of Science:

  • Oncology
  • Immunotherapy
  • Metabolomics

Background:

  • Immune checkpoint inhibitors (ICIs) have transformed cancer treatment.
  • However, a significant proportion of patients do not achieve durable responses to ICIs.
  • Understanding resistance mechanisms is crucial for improving ICI efficacy.

Purpose of the Study:

  • To investigate metabolic alterations in response to immune checkpoint blockade.
  • To identify predictive biomarkers for treatment response in advanced melanoma and renal cell carcinoma.

Main Methods:

  • Comprehensive serum metabolite profiling was performed.
  • Patients with advanced melanoma and renal cell carcinoma treated with nivolumab (anti-PD1 antibody) were analyzed.

Main Results:

  • An elevated serum kynurenine/tryptophan ratio was identified as a key metabolic alteration.
  • This metabolic shift was associated with adaptive resistance to PD1 blockade.
  • Increased kynurenine/tryptophan ratio correlated with worse overall survival.

Conclusions:

  • The kynurenine/tryptophan ratio serves as a potential biomarker for resistance to PD1 blockade.
  • Metabolic monitoring could aid in patient stratification for immunotherapy clinical trials.
  • This finding supports combination strategies involving PD1 blockade and IDO/TDO inhibitors.

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