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

CTL公司* 免疫原性 免疫学 抗原 表位 细胞毒性T细胞 头颈部鳞状细胞癌 CD8型 癌症研究 免疫系统 T细胞 癌症 免疫疗法 医学 生物 头颈部癌 内科学 体外 生物化学
作者
Sri Krishna,Peaches Ulrich,Eric Wilson,Falguni Parikh,Pooja Narang,Shanshan Yang,Amelia K. Read,Seunghee Kim‐Schulze,Jin G. Park,Marshall R. Posner,Melissa A. Wilson Sayres,Andrew G. Sikora,Karen S. Anderson
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:78 (21): 6159-6170 被引量:56
标识
DOI:10.1158/0008-5472.can-18-0163
摘要

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 (R2 = 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.
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