Potential role of radiation therapy in augmenting the activity of immunotherapy for gynecologic cancers

Abstract

Immune checkpoint inhibitors have become an area of intense interest in oncology and are actively being studied in a variety of cancer types with a wide range of success. In vitro data suggest mechanisms by which radiation can activate the immune system, and ongoing studies are exploring the potential interaction of checkpoint inhibitors with radiotherapy in both preclinical and clinical settings. Gynecologic malignancies are a heterogeneous group of tumors with varying prognoses, intrinsic immunogenicity, and potential for response to immune-based therapies. In this review, we focus on the rationale for immunotherapy and opportunities for augmentation by photon radiotherapy in cancers of the cervix, endometrium, and ovary.

Keywords: PD-1; gynecologic; immunotherapy; radiation.

Figure 1

Anti-tumor immune response. Notes: DCs process and present tumor antigens on MHC proteins. In the presence of a maturation stimulus, DCs can trigger effector or regulatory T-cell responses. Effector T-cell responses lead to a protective effect and result in tumor cell killing, while regulatory T-cell responses lead to release of T_reg (regulatory T-cells) and subsequent immunosuppressive effect mediated via various mechanisms, including PD-1 and its ligand PD-L1. Reprinted by permission from Macmillan Publishers Ltd: Nature. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–489, copyright 2011. Abbreviations: DCs, dendritic cells; MHC, major histocompatibility complex; PD-1, programmed death receptor-1; PD-L1, programmed death ligand-1.

Figure 2

The role of radiotherapy and checkpoint inhibition on immune targeting of tumor cells. Notes: Radiation enhances antigen presentation on DCs, which travel to the draining lymph node and can activate T-cell expansion. Effector T-cells in the tumor microenvironment are then able to target tumor and stromal cells for killing. However, CTLA-4 on DCs inhibits T-cell expansion and PD-1 on effector cells (including regulatory T-cells) causes T-cell apoptosis, leading to an immune-suppressive response. Thus, blockade of CTLA-4 and PD-1 (or its ligand PD-L1 or PD-L2, expressed on cancer and other cells in the tumor microenvironment) can enhance an immune response. From Spiotto M, Fu YX, Weichselbaum RR. The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. Sci Immunol. 2016;1(3):EAAG1266. Reprinted with permission from AAAS. Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DCs, dendritic cells; PD-1, programmed death receptor-1; PD-L1, programmed death ligand-1; RT, radiation therapy.