The immune microenvironment in vulvar (pre)cancer: review of literature and implications for immunotherapy

ABSTRACT

Introduction: Vulvar squamous cell carcinoma (VSCC) develops via two different pathways: TP53 mutations in a background of lichen sclerosus or a persistent infection with high-risk human papilloma virus (HPV). The latter group of tumor responds better to treatment than the non-virally induced VSCC. This may be explained by a difference in the tumor immune microenvironment (TME).

Areas covered: This review summarizes literature on TME of VSCC and its precursors, and extrapolates this to foster the development of new therapeutic strategies.

Expert opinion: Both types of VSCC and their precursors are infiltrated with variable numbers of M2 macrophages, regulatory T cells and CD8+ T cells, indicating that they express targetable tumor antigens. Type 1 T cell immunity in precursor lesions is associated with fewer recurrences and better clinical responses to immunotherapy. Escape of these lesions and progression toward VSCC is associated with the downregulation of HLA Class I, increased expression of co-inhibitory molecules, infiltration with immunosuppressive cells and the local production of immunosuppressive enzymes and cytokines. More in-depth studies of the VSCC TME are required to fully comprehend the impact of the immune system on VSCC, and subsequently to identify patients who will benefit from immunotherapeutic strategies.

KEYWORDS:

• Human papilloma virus (HPV)
• immunology
• immunotherapy
• tumor microenvironment
• usual vulvar intraepithelial neoplasia (uVIN)
• vulvar high-grade squamous intraepithelial lesion (vHSIL)
• vulvar squamous cell carcinoma (VSCC)

Article Highlights

• Two distinct types of VSCC can be identified: HPV-induced and TP53-mutated VSCC

• VSCC and its precursor are infiltrated with M2 macrophages, Tregs and CD8+ T cells

• A type 1 immune response correlates with better clinical outcomes in vHSIL

• Analysis of the microenvironment is important for immunotherapeutic strategies in VSCC

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.