Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with non-viral etiology

Abstract

Vulvar cancer is rare but incidence rates are increasing due to an aging population and higher frequencies of young women being affected. In locally advanced, metastatic or recurrent disease prognosis is poor and new treatment modalities are needed. Immune checkpoint blockade of the PD-1/PD-L1 pathway is one of the most important advancements in cancer therapy in the last years. The clinical relevance of PD-L1 expression in vulvar cancer, however, has not been studied so far. We determined PD-L1 expression, numbers of CD3+ T cells, CD20+ B cells, CD68+ monocytes/macrophages, Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages by immunohistochemistry in 103 patients. Correlation analysis with clinicopathological parameters was undertaken; the cause-specific outcome was modeled with competing risk analysis; multivariate Cox regression was used to determine independent predictors of survival. Membranous PD-L1 was expressed in a minority of tumors, defined by HPV-negativity. Its presence geographically correlated with immunocyte-rich regions of cancer islets and was an independent prognostic factor for poor outcome. Our data support the notion that vulvar cancer is an immunomodulatory tumor that harnesses the PD-1/PD-L1 pathway to induce tolerance. Accordingly, immunotherapeutic approaches might have the potential to improve outcome in patients with vulvar cancer and could complement conventional cancer treatment.

PD-L1 expression and survival in p16-negative and -positive squamous cell carcinomas of the vulva

“…By now the prognostic impact of PD-L1 in SCCV was only analyzed in a few studies. According to Sznurkowski et al, PD-L1 expression in immune cells indicates a better prognosis (Sznurkowski et al 2017), whereas PD-L1 expression in tumor cells was associated to worse outcome by Hecking et al (2017). In addition, focusing p16-negative cases only high PD-L1 expression tended to correlate with a worse OS in our study population (p = 0.071).…”

“…In addition, focusing p16-negative cases only high PD-L1 expression tended to correlate with a worse OS in our study population (p = 0.071). Correlation of PD-L1 expression with HPV-negative SCCV and poor outcome was also reported by Hecking et al (2017).…”

“…These findings are supported by investigations on oropharyngeal SCCs that could show no correlation of the HPV-status and PD-L1 (Kim et al 2016;Hong et al 2019). Otherwise, PD-L1 was correlated to HPVnegativity in SCCVs too (Hecking et al 2017). Thus, additional functional studies are needed to clarify the role HPV plays in PD-L1 induction.…”

“…High PD-L1 expression (TPS ≥ 50% and CPS ≥ 50) was observed in about 15% and was associated with a worse grading, but was independent from FIGO-stage and was also found in early cancer stages. Little is known about the PD-L1 status in SCCV, but high frequency of PD-L1 expression was also reported by a few other studies (Choschzick et al 2018;Hecking et al 2017;Thangarajah et al 2019). Currently clinical data about checkpoint-inhibitor therapy in SCCV are limited, although responsiveness was reported for single cases (Shields and Gordinier 2019;Ott et al 2019).…”

PD‐L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy

“…Prior investigations have also demonstrated tumoral PD‐L1 expression in 95% of cervical squamous intraepithelial lesions and 38–80% of cervical SCC, and increased expression has been proposed to be a consequence of HPV infection . Prior work in vulvar SCC has revealed a broader range of expression patterns within tumour cells, with some studies showing only occasional positive cases and others showing at least focal staining in the majority and diffuse tumoral expression in nearly 40% . The literature on immunohistochemical expression of IDO in cervical and vulvar neoplasia is less robust, although many studies have focused on IDO activity by either detection of serological metabolites within the kynurenine pathway or via mRNA expression of IDO in tumour cells .…”