The Effects of Gynecological Tumor Irradiation on the Immune System

Abstract

Radiobiology has evolved from a mechanistic model based on DNA damage and response factors into a more complex model that includes effects on the immune system and the tumor microenvironment (TME). Irradiation has an immunomodulatory effect that can manifest as increased anti-tumor immunity or immunosuppression. Irradiation promotes an inflammatory microenvironment through the release of pro-inflammatory cytokines and endothelial damage, which recruit immune system cells to the irradiated area. Radiation-induced immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns (DAMPs) and tumor antigens, triggers an anti-tumor immune response of both innate and adaptive immunity. Anti-tumor immunity can manifest at a distance from the irradiated area, a phenomenon known as the abscopal effect (AE), which involves dendritic cells and CD8+ T cells. Irradiation also produces an immunosuppressive effect mediated by tumor-associated macrophages (TAMs) and regulatory T lymphocytes (Tregs), which counterbalances the immunostimulatory effect. In this work, we review the mechanisms involved in the radiation-induced immune response, which support the combined treatment of RT and immunotherapy, focusing, where possible, on gynecologic cancer.

Keywords: abscopal effect; gynecological cancer; radiation-induced immune effects; radiobiology; radiotherapy.

Figure 1

Therapeutic index: the therapeutic index is established by comparing the sigmoidal dose–response curve for tumor control (red) with that for toxicity (blue). The dashed lines represent the modification of the dose-response curves due to the antitumor immune response (red) or to techniques that spare healthy tissues such as IMRT or brachytherapy (blue).

Figure 2

Linear–quadratic model. α parameter (red) represents a non-repairable lesion produced by a single irradiation event (linear component), and β parameter (blue) represents several repairable lesions produced by independent events (quadratic component).

Figure 3

Schematic representation of the complex network of the immune response pathways triggered by irradiation. DSB: double-strand DNA break; cGAS: cyclic GMP-AMP synthase; STING: stimulator of interferon genes; IFN: interferon; CCL2, CCL19, CCL21, and CCL22: chemokines; TAAs: tumor antigens; ICD: immunogenic cell death; ATP: adenosine triphosphate; CALRT: calreticulin; HMGB1: high-mobility group protein B1; P2X, CD91, and TRL4: pattern recognition receptors; DC: dendritic cell; MHC: major histocompatibility complex; TCR: T-cell receptor; TNFα: tumor necrosis factor-alpha; ROS: reactive oxygen species; IL: interleukin; TGFβ: transforming growth factor-beta; NFκB: nuclear factor kappa B; TAM: tumor-associated macrophage; TAN: tumor-associated neutrophil; Treg: regulatory T lymphocyte.