B7-H1 Expression Model for Immune Evasion in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma

Abstract

Human papillomavirus (HPV) is associated with oropharyngeal squamous cell carcinomas. Persistent viral infection is postulated to lead to carcinogenesis, although infection of benign adjacent epithelium is not typically observed. It is known that immune evasive tumor cells can provide an ideal niche for a virus. The B7-H1/ PD-1 cosignaling pathway plays an important role in viral immune evasion by rendering CD8? cytotoxic T cells anergic. We hypothesized that HPV-related oropharyngeal squamous cell carcinomas express B7-H1 as a mechanism for immune evasion. A tissue microarray was utilized, for which HPV E6/E7 mRNA by in situ hybridization was previously performed. Immunohistochemistry was performed to detect B7-H1 and staining was characterized by pattern, distribution, and intensity. B7-H1 was expressed by 84 of the 181 (46.4 %) cases. Both tumor cell membranous and cytoplasmic expression were present and cytoplasmic expression was identified in some peritumoral lymphocytes. Expression was analyzed in several different ways and then considered binarily as positive versus negative. Tumors expressing B7-H1 were more likely to be HPV positive (49.2 vs. 34.1 %, p = 0.08). B7-H1 expression showed no correlation with disease recurrence in the entire cohort (OR = 1.09, p = 0.66), HPV positive cohort (OR = 0.80, p = 0.69) or HPV negative cohort (OR = 2.02, p = 0.22). However, B7-H1 expression intensity did correlate with the development of distant metastasis (p = 0.03), and B7-H1 intensity of 3? (versus all other staining) showed a strong trend towards distant metastasis in the HPV positive (OR = 6.67, p = 0.13) and HPV negative (OR = 9.0, p = 0.13) cohorts. There was no correlation between B7-H1 expression and patient survival for any of the different ways in which staining was characterized, whether binarily, by distribution, intensity, or combined scores. B7-H1 is expressed in the majority of oropharyngeal squamous cell carcinomas with transcriptionally-active HPV. This suggests that B7-H1 expression by tumor cells may play a role in harboring persistent HPV infection.

Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma

“…Another study evaluating oropharyngeal SCC showed that PD-L1 was expressed in 49.2% and 34.1% of HPV mRNA-positive and -negative cases, respectively. No correlation was evident between PD-L1 status and survival [49]. A more recent study of 340 NSCLC patients, including 178 SCC patients, found that the PD-L1 mRNA and protein expression levels, as assessed via in situ hybridization and tissue microarray, respectively, were in agreement, and that high PD-L1 expression levels were associated with elevated TILs and better survival [50].…”

PD-1/PD-L1 biology and immunotherapy in HPV-positive oral cancers

“…But very little literature has been published correlating HPV positivity and oral cancer lesions with immune-checkpoint inhibitors. Two different studies by LyfordPike et al and Upko et al have shown that HPVpositive oral cancer cases overexpressed PD-L1 when compared with HPV negative cases [11,12]. They also established that HPV-positive cases possess PD-1 overexpressing CD8, CD4 and TILs in their tumor microenvironment.…”

Immunity in Head and Neck Cancer

“…Head and neck cancers not associated with HPV infection likely also co-opt immune regulatory mechanisms to facilitate their progression. Increased PD-L1 expression similarly has been detected on tobacco-and alcohol-induced SCCs of the head and neck (11,(13)(14)(15)(16), as well as other virally mediated tumors, including nasopharyngeal carcinoma and natural killer T (NKT)-cell lymphoma (17). HPV-targeted vaccination is recommended for adolescent boys and girls to prevent incident HPV infection.…”

“…One study identified PD-1 þ -infiltrating T cells as a favorable prognostic factor in HPV-associated oropharyngeal cancer (28). In other studies of patients with cancers of the oral cavity and oropharynx, PD-L1 expression was not prognostic (13), or was indicative of distant metastases but not local recurrence or overall survival (16).…”