TY - JOUR
T1 - Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer
AU - Krishna, Sri
AU - Ulrich, Peaches
AU - Wilson, Eric
AU - Parikh, Falguni
AU - Narang, Pooja
AU - Yang, Shanshan
AU - Read, Amelia K.
AU - Kim-Schulze, Seunghee
AU - Park, Jin
AU - Posner, Marshall
AU - Wilson Sayres, Melissa
AU - Sikora, Andrew
AU - Anderson, Karen
N1 - Funding Information:
We thank Marika Hopper, Padhmavathy Yuvaraj from Anderson lab for help with cell culture and R-ELISA analysis, and Samantha Cotsmire (Biodesign CIVV, ASU) for helpful advice. We thank Yasin S¸enbabaoglu (Genentech) for input on ssGSEA analysis. S. Krishna acknowledges funding support from ASU School of Graduate Education Dissertation Completion Fellowship, and School of Biological and Health Systems Engineering, ASU. We also thank the Human Immune Monitoring Center, Ichan School of Medicine for patient sample processing and management. This work was supported by institutional funds from Arizona State University.
Funding Information:
A. Sikora reports receiving a commercial research grant from Tessa Therapeutics. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
2018 American Association for Cancer Research.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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 HPVþ HNSCC. Here we assess immunogenicity of HPV16-specific CD8þ 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 HPVþ HNSCC than in healthy controls (>3-fold; P ¼ 0.026). Patient-derived E2, E6, and E7 peripheral CTLs exhibited heterogeneity in dysfunctional phenotypes. Immunoge-nomic analyses of 119 HNSCC transcriptomes revealed high T-cell infiltration and dysfunction in HPVþ HNSCC and correlation of HPV antigen expression with T-cell exhaustion gene signatures. Indoleamine 2,3-dioxygenase (IDO-1) was strongly expressed in HPVþ HNSCC versus HPV HNSCC (P ¼ 0.001) and correlated with E7 expression (R2 ¼ 0.84; P ¼ 0.033). Combination treatment with PD-1 blockade and IDO-1 inhibition overcame profound CTL-dysfunction, enhancing HPVþ HNSCC sensitivity to CTL-cytotoxicity in vitro (up to 10-fold in E7-CTLs, P ¼ 0.011). Our findings implicate mechanisms of T-cell escape in HPVþ 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 HPVþ 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 HPVþ HNSCC.
AB - 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 HPVþ HNSCC. Here we assess immunogenicity of HPV16-specific CD8þ 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 HPVþ HNSCC than in healthy controls (>3-fold; P ¼ 0.026). Patient-derived E2, E6, and E7 peripheral CTLs exhibited heterogeneity in dysfunctional phenotypes. Immunoge-nomic analyses of 119 HNSCC transcriptomes revealed high T-cell infiltration and dysfunction in HPVþ HNSCC and correlation of HPV antigen expression with T-cell exhaustion gene signatures. Indoleamine 2,3-dioxygenase (IDO-1) was strongly expressed in HPVþ HNSCC versus HPV HNSCC (P ¼ 0.001) and correlated with E7 expression (R2 ¼ 0.84; P ¼ 0.033). Combination treatment with PD-1 blockade and IDO-1 inhibition overcame profound CTL-dysfunction, enhancing HPVþ HNSCC sensitivity to CTL-cytotoxicity in vitro (up to 10-fold in E7-CTLs, P ¼ 0.011). Our findings implicate mechanisms of T-cell escape in HPVþ 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 HPVþ 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 HPVþ HNSCC.
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U2 - 10.1158/0008-5472.CAN-18-0163
DO - 10.1158/0008-5472.CAN-18-0163
M3 - Article
C2 - 30154146
AN - SCOPUS:85055899825
SN - 0008-5472
VL - 78
SP - 6159
EP - 6170
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -