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.

A Gene Signature Identifying CIN3 Regression and Cervical Cancer Survival

“…Immune and stromal cells dominate the microenvironment in CIN and cervical cancer. In the last decade, a better understanding of HPV tumor–host immune system interactions (reviewed in [ 25 ]) and the development of new immune checkpoint targeting strategies have led to renewed interest in immunotherapy for cervical cancer patients. To aid in the growing challenge of reducing overtreatment of CIN2-3 lesions (induced by, e.g., implementation of HPV-based screening and a higher proportion of vaccinated women), we aimed to identify immune-related biomarkers that predict CIN regression.…”

Genomic Signatures in HPV-Associated Tumors

“…In addition to the DNA repair related, cell-intrinsic radiosensitivity mechanisms, other possibilities include incomplete TP53 inactivation [ 34 ], expression of radiosensitizing E6 isoforms [ 74 ], or prolonged G2/M arrest [ 35 ]; there are also cell-extrinsic proposed mechanisms involving the tumor microenvironment, such as decreased tumor hypoxia and improved immunoreactivity, which are nicely reviewed elsewhere [ 39 , 75 , 76 ].…”

Molecular Markers to Predict Prognosis and Treatment Response in Uterine Cervical Cancer

“…A network of immune and endothelial cells, fibroblasts, signaling proteins and extracellular matrix molecules within the tumor and the surrounding tissue constitutes the TME [233]. In that context, immunosuppressive and immunogenic tumor-infiltrating immune cells influence the prognostic landscape in cervical cancer, which is highly related to and modulated by HPV [234] (Figure 4).…”

“…For instance, E5 inhibits the transport of major histocompatibility complex (MHC) molecules to the cell surface, which present either viral or tumor-associated antigens [244,245]. Moreover, E6 and E7 interact with type I IFN pathways, mitigating antiviral programs of immune response or upregulating PD-L1 expression (E7) to facilitate lymphocyte dysfunction [234,246].…”