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Frameshift events predict anti-PD-1/L1 response in head and neck cancer

Glenn J Hanna1, Patrick Lizotte1,2, Megan Cavanaugh1,2

  • 1Department of Medical Oncology, and.

JCI Insight
|February 23, 2018
PubMed

Insights

Identifying biomarkers for anti-PD-1/L1 therapy in head and neck cancer is crucial. Higher tumor mutational burden and specific gene mutations in virus-negative tumors predict better response to immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Programmed cell death protein 1 (PD-1) inhibitors show promise for squamous cell carcinoma of the head and neck (SCCHN).
  • Objective response rates are limited, and Programmed cell death ligand 1 (PD-L1) expression is not a definitive predictor of response.
  • There is a need for novel biomarkers to guide anti-PD-1/L1 therapy selection in SCCHN.

Purpose of the Study:

  • To identify predictive biomarkers for anti-PD-1/L1 therapy in SCCHN patients.
  • To investigate the relationship between tumor mutational burden (TMB), viral status, gene mutations, and immune cell infiltrates with treatment response.
  • To explore potential biomarkers beyond PD-L1 expression.

Main Methods:

  • An observational cohort study of 126 SCCHN patients treated with anti-PD-1/L1 therapy.
  • Tumor sequencing, fluorescence-activated cell sorting, and immunohistochemistry were performed for immunoprofiling.
  • Analysis of overall survival (OS), TMB, gene mutations (NOTCH1, SMARCA4), and immune markers (CD8+, TIM-3, LAG-3).

Main Results:

  • Low objective response rates (14%) were observed.
  • Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit in virus-negative tumors (P < 0.01).
  • Somatic frameshift events in tumor suppressor genes and mutations in NOTCH1/SMARCA4 were associated with response in virus-negative SCCHN (P = 0.03).
  • TIM-3/LAG-3 coexpression was higher in non-responders.

Conclusions:

  • Higher TMB and CD8+ T cell infiltrates are promising biomarkers for predicting anti-PD-1/L1 therapy response in virus-negative SCCHN.
  • Somatic frameshift events in tumor suppressor genes may also predict response.
  • Further research is warranted to validate these biomarkers for clinical application in SCCHN immunotherapy.
Keywords:
GeneticsHead & neck cancerImmunotherapyMolecular geneticsOncology

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