Immunotherapeutic Approaches for the Treatment of HPV-Associated (Pre-)Cancer of the Cervix, Vulva and Penis

Abstract

Human papillomavirus (HPV) infection drives tumorigenesis in almost all cervical cancers and a fraction of vulvar and penile cancers. Due to increasing incidence and low vaccination rates, many will still have to face HPV-related morbidity and mortality in the upcoming years. Current treatment options (i.e., surgery and/or chemoradiation) for urogenital (pre-)malignancies can have profound psychosocial and psychosexual effects on patients. Moreover, in the setting of advanced disease, responses to current therapies remain poor and nondurable, highlighting the unmet need for novel therapies that prevent recurrent disease and improve clinical outcome. Immunotherapy can be a useful addition to the current therapeutic strategies in various settings of disease, offering relatively fewer adverse effects and potential improvement in survival. This review discusses immune evasion mechanisms accompanying HPV infection and HPV-related tumorigenesis and summarizes current immunotherapeutic approaches for the treatment of HPV-related (pre-)malignant lesions of the uterine cervix, vulva, and penis.

Keywords: cervical cancer; human papillomavirus; immunotherapy; penile cancer; urogenital; vulvar cancer.

Figure 1

This figure shows an adapted version of the cancer immunity cycle to illustrate the intracellular and extracellular evasion strategies of human papillomavirus (HPV). (1) Release of viral antigens and neoantigens; (2) cancer antigen presentation (chemokine CCL20 (CCL20), interleukin-6 (IL-6), prostaglandin E2 (PGE2), receptor activator of NF-KB ligand (RANKL), Langerhans cells (LCs), and dendritic cells (DCs)); (3) priming and activation (major histocompatibility complex II (MHC-II), programmed death-ligand-1 (PD-L1), regulatory T cells (Tregs), and cytotoxic T-lymphocyte-associated protein (CTLA)); (4) tumor infiltration (pro-inflammatory macrophages (M1 MΦ), granzyme B (GrB), T-helper cells 1 (Th1s), anti-inflammatory macrophages (M2 MΦ), and myeloid-derived suppressor cells (MDSCs)); (5) recognition of tumor cells (antigen-processing machinery (APM) modification); (6) killing of tumor cells (PD-1 receptor (PD-1), T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), transforming growth factor (TGF-β), indoleamine 2,3-dioxygenase (IDO)). Created with BioRender.com (last accessed on 15 February 2022).

Figure 2

This figure highlights examples of strategies that are currently being employed in preclinical and clinical settings to restore immune function in human papillomavirus (HPV) infected tumor microenvironment. The strategies marked in red are discussed in this review. Toll-like receptor (TLR); cytotoxic T-lymphocyte-associated protein (CTLA); vascular endothelial growth factor (VEGF); tumor-infiltrating lymphocytes (TIL) therapy; chimeric antigen receptor T-cells (CAR-T) therapy; programmed death-ligand-1 (PD-L1); PD-1 receptor (PD-1); T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3); lymphocyte activation gene-3 (LAG-3); indoleamine 2,3-dioxygenase (IDO). Created with BioRender.com (last accessed on 15 February 2022).