Driving Immune Responses in the Ovarian Tumor Microenvironment

Abstract

Ovarian cancer is the leading cause of death among gynecological neoplasms, with an estimated 14,000 deaths in 2019. First-line treatment options center around a taxane and platinum-based chemotherapy regimen. However, many patients often have recurrence due to late stage diagnoses and acquired chemo-resistance. Recent approvals for bevacizumab and poly (ADP-ribose) polymerase inhibitors have improved treatment options but effective treatments are still limited in the recurrent setting. Immunotherapy has seen significant success in hematological and solid malignancies. However, effectiveness has been limited in ovarian cancer. This may be due to a highly immunosuppressive tumor microenvironment and a lack of tumor-specific antigens. Certain immune cell subsets, such as regulatory T cells and tumor-associated macrophages, have been implicated in ovarian cancer. Consequently, therapies augmenting the immune response, such as immune checkpoint inhibitors and dendritic cell vaccines, may be unable to properly enact their effector functions. A better understanding of the various interactions among immune cell subsets in the peritoneal microenvironment is necessary to develop efficacious therapies. This review will discuss various cell subsets in the ovarian tumor microenvironment, current immunotherapy modalities to target or augment these immune subsets, and treatment challenges.

Keywords: adaptive immunity; cancer therapeutics; innate immunity; ovarian cancer; tumor microenvironment.

Figure 1

Driving Immune Responses in the Ovarian Tumor Microenvironment. Immune cells are present intratumorally and in the ovarian tumor microenvironment. Strategies discussed throughout the paper have been summarized above the corresponding cell type. Attempts to improve T cell functionality in the ovarian TME include Immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, and anti-CTLA4, which have been used in clinical trials to reduce inhibitory signaling. Similarly, T cells with chimeric antigen receptors (CAR-Ts) against folate receptor-alpha (FRα), MUC-16, and mesothelin have been tested in clinical trials in order to recognize tumor-associated antigens. CAR-Ts have been tested in vitro against novel antigens. CAR-T: Chimeric antigen receptor T-cell. ICI, Immune checkpoint inhibitor; CAR-NK, Chimeric antigen receptor-Natural Killer cell; Mφ, Macrophage; I.p., Intraperitoneal; GM-CSF, Granulocyte-monocyte colony stimulating factor; ApoE, ApolipoproteinE; MDSC, Myeloid-derived suppressor cell. Created with Biorender.com.