Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma

• Published in: Cell reports. Medicine Vol. 2; no. 10; p. 100411
• Main Authors: Liu, Sixue, Knochelmann, Hannah M., Lomeli, Shirley H., Hong, Aayoung, Richardson, Mary, Yang, Zhentao, Lim, Raymond J., Wang, Yan, Dumitras, Camelia, Krysan, Kostyantyn, Timmers, Cynthia, Romeo, Martin J., Krieg, Carsten, O’Quinn, Elizabeth C., Horton, Joshua D., Dubinett, Steve M., Paulos, Chrystal M., Neskey, David M., Lo, Roger S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.10.2021; Elsevier
• Subjects: Antineoplastic Agents, Immunological - therapeutic use; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - surgery; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - immunology; FLT4/PTEN/PPARG/CDKN2A/YAP1/JAK2; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; head-and-neck cancer/oral-cavity SCC; Humans; Immune Checkpoint Inhibitors - therapeutic use; Janus Kinase 2 - genetics; Janus Kinase 2 - immunology; Mouth Neoplasms - drug therapy; Mouth Neoplasms - genetics; Mouth Neoplasms - immunology; Mouth Neoplasms - surgery; multiplex immunofluorescence; Mutation; neoadjuvant anti-PD-1/L1 therapy; Neoadjuvant Therapy - methods; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - surgery; Nivolumab - therapeutic use; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; recurrence-free survival; response, resistance, and recurrence; Survival Analysis; T cell repertoire; T regulatory to Th17 ratio; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 Cells - pathology; Treatment Outcome; tumor mutational burden; tumor phylogeny; Vascular Endothelial Growth Factor Receptor-3 - genetics; Vascular Endothelial Growth Factor Receptor-3 - immunology; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - immunology; T regulatory to Th17 ratio; neoadjuvant anti-PD-1/L1 therapy; FLT4/PTEN/PPARG/CDKN2A/YAP1/JAK2; tumor mutational burden; recurrence-free survival; multiplex immunofluorescence; T cell repertoire; head-and-neck cancer/oral-cavity SCC; response, resistance, and recurrence; tumor phylogeny
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2021.100411

Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer. [Display omitted] •FLT4 nsSNVs favor response; CDKN2A nsSNVs favor non-response; high TMB improves RFS•Recurrences select for CN loss in PTEN, JAK2 and/or gain in YAP1, MDM2, PPARG•T cell clones (blood) diversify and preexisting clones (tumors) expand with response•High ratios of TREG/Th17 in pretreatment blood predict innate resistance Liu et al. nominate multi-omic correlates of response, recurrence, and survival in individuals treated with neoadjuvant anti-PD-1 therapy for resectable, locally advanced, oral cavity SCC. Future validation of blood- and tumor-based biomarkers and mechanistic insights have implications for neoadjuvant and adjuvant management of individuals with systemic treatment-naive resectable disease.