Human Papilloma Virus Specific Immunogenicity and Dysfunction of CD8 + T Cells in Head and Neck Cancer.

Autor:	Krishna S; Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, Arizona.; School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona., Ulrich P; Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, Arizona.; School of Life Sciences, Arizona State University, Tempe, Arizona., Wilson E; Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, Arizona., Parikh F; Department of Otolaryngology and Head and Neck Surgery, Baylor College of Medicine, Houston, Texas., Narang P; School of Life Sciences, Arizona State University, Tempe, Arizona., Yang S; Biodesign Institute Bioinformatics Core Facility, Arizona State University, Tempe, Arizona., Read AK; Department of Otolaryngology, Stanford University, Stanford, California., Kim-Schulze S; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai Medical Center, New York, New York., Park JG; Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, Arizona., Posner M; Tisch Cancer institute, Icahn School of Medicine at Mount Sinai Medical Center, New York, New York., Wilson Sayres MA; School of Life Sciences, Arizona State University, Tempe, Arizona.; Center for Evolution and Medicine, Arizona State University, Tempe, Arizona., Sikora A; Department of Otolaryngology and Head and Neck Surgery, Baylor College of Medicine, Houston, Texas., Anderson KS; Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, Arizona. karen.anderson.1@asu.edu.; School of Life Sciences, Arizona State University, Tempe, Arizona.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Nov 01; Vol. 78 (21), pp. 6159-6170. Date of Electronic Publication: 2018 Aug 28.
DOI:	10.1158/0008-5472.CAN-18-0163
Abstrakt:	Human papillomavirus subtype 16 (HPV16) is the primary cause of an increasing number of head and neck squamous cell carcinomas (HNSCC), providing strong rationale for T-cell immune therapies against HPV + HNSCC. Here we assess immunogenicity of HPV16-specific CD8 + T cells (CTL) and characterize HPV-specific mechanisms of T-cell dysfunction. We identified 16 strong and 29 moderately immunogenic CTL-epitopes from HPV16 E2, E6, and E7 antigens restricted by 12 common HLA class I alleles. E2-specific CTL-reactivity was higher in patients with HPV + HNSCC than in healthy controls (>3-fold; P = 0.026). Patient-derived E2, E6, and E7 peripheral CTLs exhibited heterogeneity in dysfunctional phenotypes. Immunogenomic analyses of 119 HNSCC transcriptomes revealed high T-cell infiltration and dysfunction in HPV + HNSCC and correlation of HPV antigen expression with T-cell exhaustion gene signatures. Indoleamine 2,3-dioxygenase (IDO-1) was strongly expressed in HPV + HNSCC versus HPV - HNSCC ( P = 0.001) and correlated with E7 expression ( R 2 = 0.84; P = 0.033). Combination treatment with PD-1 blockade and IDO-1 inhibition overcame profound CTL-dysfunction, enhancing HPV + HNSCC sensitivity to CTL-cytotoxicity in vitro (up to 10-fold in E7-CTLs, P = 0.011). Our findings implicate mechanisms of T-cell escape in HPV + HNSCC, wherein high tumoral HPV-antigen load results in high expression of immune dysfunction genes on tumor cells (e.g., IDO-1), and dysfunction of HPV-specific CTLs (e.g., E7, E2-CTLs). The HPV16 CTL-epitopes identified in this study, in combination with blockade of HPV + HNSCC-specific PD-1/IDO-1 checkpoints, may be useful for targeted immunotherapy. Significance: This study evaluates the HPV antigen T-cell immunogenicity role of inhibitory receptors and other exhaustion markers in the cytotoxic function of HPV antigen-specific CTLs and identifies combined inhibition of PD-1/IDO-1 as a strategy to enhance CTL targeting of HPV + HNSCC. Cancer Res; 78(21); 6159-70. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu