Cervical Cancer Immunotherapy: Facts and Hopes

Abstract

It is a sad fact that despite being almost completely preventable through human papillomavirus (HPV) vaccination and screening, cervical cancer remains the fourth most common cancer to affect women worldwide. Persistent high-risk HPV (hrHPV) infection is the primary etiologic factor for cervical cancer. Upward of 70% of cases are driven by HPV types 16 and 18, with a dozen other hrHPVs associated with the remainder of cases. Current standard-of-care treatments include radiotherapy, chemotherapy, and/or surgical resection. However, they have significant side effects and limited efficacy against advanced disease. There are a few treatment options for recurrent or metastatic cases. Immunotherapy offers new hope, as demonstrated by the recent approval of programmed cell death protein 1-blocking antibody for recurrent or metastatic disease. This might be augmented by combination with antigen-specific immunotherapy approaches, such as vaccines or adoptive cell transfer, to enhance the host cellular immune response targeting HPV-positive cancer cells. As cervical cancer progresses, it can foster an immunosuppressive microenvironment and counteract host anticancer immunity. Thus, approaches to reverse suppressive immune environments and bolster effector T-cell functioning are likely to enhance the success of such cervical cancer immunotherapy. The success of nonspecific immunostimulants like imiquimod against genital warts also suggest the possibility of utilizing these immunotherapeutic strategies in cervical cancer prevention to treat precursor lesions (cervical intraepithelial neoplasia) and persistent hrHPV infections against which the licensed prophylactic HPV vaccines have no efficacy. Here, we review the progress and challenges in the development of immunotherapeutic approaches for the prevention and treatment of cervical cancer.

Figure 1:. Schematic overview of cancer immunotherapies to target cervical cancer.

A). Strategies to generate and enhance cervical cancer specific T Cells. G-CSF: Granulocyte Colony Stimulating Factor. B). Strategies to augment effector immune cells in the TME. GITR: Glucocorticoid-Induced TNFR-Related protein; TLR3: Toll-Like Receptor 3; PD-1: Programmed cell Death protein 1; TIM3: T cell Immunoglobulin and Mucin-domain containing 3; CTLA-4: Cytotoxic T Lymphocyte Associated Protein 4; LAG3: Lymphocyte Activation Gene 3; A2AR: Adenosine 2A Receptor. C). Conventional cervical cancer therapies. D) Strategies to target immunosuppressive factors in the TME. MET: Mesenchymal Epithelial Transition factor; PI3K: Phosphoinositide 3-kinase; COX: Cyclooxygenase; PD-L1: Programmed cell Death protein Ligand; PARP: Poly ADP Ribose Polymerase; FAP: Fibroblast Activation Protein; VEGF: Vascular Endothelial Growth Factor; IDO: Indoleamine 2,3-dioxygenase. Figure created with BioRender.com.