Tumor Immunity and Immunotherapy for HPV-Related Cancers

Abstract

Human papillomavirus (HPV) infection drives tumorigenesis in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Genetic and epidemiologic evidence has highlighted the role of immunosuppression in the oncogenesis of HPV-related malignancies. Here we review how HPV modulates the immune microenvironment and subsequent therapeutic implications. We describe the landscape of immunotherapies for these cancers with a focus on findings from early-phase studies exploring antigen-specific treatments, and discuss future directions. Although responses across these studies have been modest to date, a deeper understanding of HPV-related tumor biology and immunology may prove instrumental for the development of more efficacious immunotherapeutic approaches. SIGNIFICANCE: HPV modulates the microenvironment to create a protumorigenic state of immune suppression and evasion. Our understanding of these mechanisms has led to the development of immunomodulatory treatments that have shown early clinical promise in patients with HPV-related malignancies. This review summarizes our current understanding of the interactions of HPV and its microenvironment and provides insight into the progress and challenges of developing immunotherapies for HPV-related malignancies.

Figure 1:. Cell-intrinsic mechanisms of HPV immune modulation.

Infection by HPV and expression of HPV proteins E5, E6, and E7 can lead to immune suppression, evasion, and resistance. HPV E7 has been shown to downregulate the cGAS STING pathway, an important innate response pathway to viral DNA that induces the expression of type I IFN genes, by directly inhibiting STING (left). HPV E6 can also dampen type I IFN gene expression by inhibiting the IFN regulatory factor IRF3. HPV E5 inhibits transport of MHC to the cell surface, which may be bound to either viral or tumor antigens, by alkalization of late endosomes. Finally, overexpression of E7 in a preclinical cervical cancer model has been shown to upregulate the PD-L1 immune checkpoint.

Figure 2:. HPV immune modulation of the tumor microenvironment.

HPV infected tumor cells promote an immunosuppressive microenvironment through several mechanisms. Downregulation of antigen presentation on MHC by HPV E5 or mutations in antigen presentation pathway genes leads to decreased recognition by effector T cells. Upregulation of the PD-L1 immune checkpoint on infected tumor cells can lead to inhibition of cytolytic T cell activity. HPV also modulates HLA expression to engage NK cell inhibitory receptors, for example through the interaction of HLA-E molecules with NKG2A. There is also evidence of HPV-antigen specific FOXP3+ T regulatory cells, which function to suppress both CD8+ and CD4+ cells in the tumor microenvironment. CD4+ cells are typically skewed towards a Th2 response due to an upregulation of Th2 cytokines, which stimulates a humoral response. In some HPV-positive malignancies, a high frequency of antibodies specific to E2, E6, and E7 is also detected.

Figure 3:. Strategies of adoptive cell therapy in HPV-positive malignancies.

A. Polyclonal TILs are collected from patients, expanded ex-vivo and re-infused into patients. B. An HLA matched, antigen-specific T-cell receptor is identified and cloned and infused into patients for TCR therapy. TCRs in this approach are highly dependent on the patient HLA haplotype C. CAR T cells are dependent on extracellular antigens and circumvent the HLA matching problem seen with TCR based therapies