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

Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-y...

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Bibliographic Details
Published inJCI insight Vol. 3; no. 4
Main Authors Hanna, Glenn J, Lizotte, Patrick, Cavanaugh, Megan, Kuo, Frank C, Shivdasani, Priyanka, Frieden, Alexander, Chau, Nicole G, Schoenfeld, Jonathan D, Lorch, Jochen H, Uppaluri, Ravindra, MacConaill, Laura E, Haddad, Robert I
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 22.02.2018
Subjects
Genetics
Oncology
Head & neck cancer
Molecular genetics
Immunotherapy
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Summary:Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.
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Authorship note: LEM and RIH are co–senior authors and contributed equally to this work.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.98811