Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

Abstract

Recent advances in the understanding of immune function and the interactions with tumour cells have led to the development of various cancer immunotherapies and strategies for specific cancer types. However, despite some stunning successes with some malignancies such as melanomas and lung cancer, most patients receive little or no benefit from immunotherapy, which has been attributed to the tumour microenvironment and immune evasion. Although the US Food and Drug Administration have approved immunotherapies for some cancers, to date, only the anti-angiogenic antibody bevacizumab is approved for the treatment of epithelial ovarian cancer. Immunotherapeutic strategies for ovarian cancer are still under development and being tested in numerous clinical trials. A detailed understanding of the interactions between cancer and the immune system is vital for optimisation of immunotherapies either alone or when combined with chemotherapy and other therapies. This article, in two main parts, provides an overview of: (1) components of the normal immune system and current knowledge regarding tumour immunology, biology and their interactions; (2) strategies, and targets, together with challenges and potential innovative approaches for cancer immunotherapy, with attention given to epithelial ovarian cancer.

Keywords: MUC16; adoptive T-cell therapy; checkpoint inhibition; glycans; immune system; immunotherapy; ovarian cancer; tumour microenvironment.

Figure 1

T-cell receptor (TCR) complex composed of α and β chains for antigen recognition, associated noncoavalently with CD3γε and CD3δε heterodimers, and a CD3ζ (CD247) homodimer. V, C = variable, constant immunoglobulin-like extracellular domains. i = ITAM (immune receptor tyrosine-based activation motif).

Figure 2

General structures of some common cancer immunotherapeutic agents or components. (a) IgG mAb. Fab = antigen binding fragment, Fc = complement and Fc receptor binding fragment. (b) Single chain variable fragment (scFv) structure, derived from the heavy and light chains of the variable antigen binding domain of a mAb. (The V_L and V_H units may be engineered in either order). (c) Tandem scFv, bispecific T-cell engager (BiTE) structure. C = constant region, V = variable region, H = heavy chain, L = light chain.

Figure 3

Chimeric antigen receptor (CAR) designs. Target binding in all generations has mostly used a scFv, linked via a hinge domain (mostly derived from IgG C_H1C_H2 or C_H2C_H3 regions) to a transmembrane region (mostly from CD3ξ) and a cytoplasmic region for TCR signaling from CD3ξ. The second generation added an intracellular costimulatory domain, and the third generation added two costimulatory domains. The costimulatory domains were usually CD28, CD137 (4-1BB/TNFRSF9), or CD134 (OX40). The fourth generation (TRUCKs) are engineered to release an inducible payload, usually IL-12, and may also contain a controllable on-off switch, or suicide gene. i = ITAM (immune receptor tyrosine-based activation motif).