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

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 21; pp. 6159 - 6170
• Main Authors: Krishna, Sri, Ulrich, Peaches, Wilson, Eric, Parikh, Falguni, Narang, Pooja, Yang, Shanshan, Read, Amelia K, Kim-Schulze, Seunghee, Park, Jin G, Posner, Marshall, Wilson Sayres, Melissa A, Sikora, Andrew, Anderson, Karen S
• Format: Journal Article
• Language: English
• Published: United States 01.11.2018
• Subjects: Aged; Alleles; CD8-Positive T-Lymphocytes - cytology; Epitope Mapping; Epitopes - immunology; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - virology; Histocompatibility Antigens Class I - metabolism; Human papillomavirus 16 - immunology; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Leukocytes, Mononuclear - cytology; Middle Aged; Papillomavirus E7 Proteins - immunology; Papillomavirus Infections - immunology; Phenotype; T-Lymphocytes, Cytotoxic - cytology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-0163

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; = 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 ( = 0.001) and correlated with E7 expression ( = 0.84; = 0.033). Combination treatment with PD-1 blockade and IDO-1 inhibition overcame profound CTL-dysfunction, enhancing HPV HNSCC sensitivity to CTL-cytotoxicity (up to 10-fold in E7-CTLs, = 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. 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. .