Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer

Sri Krishna, Peaches Ulrich, Eric Wilson, Falguni Parikh, Pooja Narang, Shanshan Yang, Amelia K. Read, Seunghee Kim-Schulze, Jin Park, Marshall Posner, Melissa Wilson Sayres, Andrew Sikora, Karen Anderson

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6159-6170
Number of pages12
JournalCancer Research
Volume78
Issue number21
DOIs
StatePublished - Nov 1 2018

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Papillomaviridae
Head and Neck Neoplasms
T-Lymphocytes
Human papillomavirus 16
Antigens
T-Lymphocyte Epitopes
Carcinoma, squamous cell of head and neck
Indoleamine-Pyrrole 2,3,-Dioxygenase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer. / Krishna, Sri; Ulrich, Peaches; Wilson, Eric; Parikh, Falguni; Narang, Pooja; Yang, Shanshan; Read, Amelia K.; Kim-Schulze, Seunghee; Park, Jin; Posner, Marshall; Wilson Sayres, Melissa; Sikora, Andrew; Anderson, Karen.

In: Cancer Research, Vol. 78, No. 21, 01.11.2018, p. 6159-6170.

Research output: Contribution to journalArticle

Krishna, S, Ulrich, P, Wilson, E, Parikh, F, Narang, P, Yang, S, Read, AK, Kim-Schulze, S, Park, J, Posner, M, Wilson Sayres, M, Sikora, A & Anderson, K 2018, 'Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer', Cancer Research, vol. 78, no. 21, pp. 6159-6170. https://doi.org/10.1158/0008-5472.CAN-18-0163
Krishna, Sri ; Ulrich, Peaches ; Wilson, Eric ; Parikh, Falguni ; Narang, Pooja ; Yang, Shanshan ; Read, Amelia K. ; Kim-Schulze, Seunghee ; Park, Jin ; Posner, Marshall ; Wilson Sayres, Melissa ; Sikora, Andrew ; Anderson, Karen. / Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer. In: Cancer Research. 2018 ; Vol. 78, No. 21. pp. 6159-6170.
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AU - Parikh, Falguni

AU - Narang, Pooja

AU - Yang, Shanshan

AU - Read, Amelia K.

AU - Kim-Schulze, Seunghee

AU - Park, Jin

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AU - Wilson Sayres, Melissa

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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.

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