Immunomodulation by radiotherapy in tumour control and normal tissue toxicity

Abstract

Radiotherapy (RT) is a highly effective anti-cancer treatment that is delivered to over half of all cancer patients. In addition to the well documented direct cytotoxic effects, RT can induce immunomodulatory effects to the tumour and surrounding tissues. These effects are thought to underlie the so-called 'abscopal responses', where RT generates systemic antitumour immunity outside of the irradiated tumour. In addition, RT may also result in an inflammatory immune response in the normal tissues surrounding the tumour. The full scope of these immune changes remains unclear but is likely to involve multiple tissue components and immune mediators. These include immune cells, the extracellular matrix, endothelial and epithelial cells and a myriad of chemokines and cytokines, including TGFβ, which is known to play a key role. In normal tissues exposed to RT during cancer therapy, acute immune changes may ultimately lead to chronic inflammation and RT-induced toxicity and organ dysfunction, which limits the quality of life of cancer survivors. Here, we discuss the emerging understanding of RT-induced immune effects with a particular focus on the lung and gut and the potential immune cross-talk that occurs between these tissues.

Impacts of the STING‐IFNAR1‐STAT1‐IRF1 pathway on the cellular immune reaction induced by fractionated irradiation

“…It has also been reported that radiation‐induced immune responses of cancer cells occur through PBMCs, including macrophages, dendritic cells, and CD4 + cells, in cancer tissues 27 . We confirmed that the migration of all these cell fractions was increased by FIR in vitro and that the intracellular immune response and cytokine production were increased in a STING‐dependent manner.…”

Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma

“…These locoregional treatments not only can destroy primary tumors but also facilitate antitumor immunity by releasing the neoplasm antigens from killed tumor cells (84). Interestingly, ionizing radiation exerts an abscopal effect in several tumors, such as lung adenocarcinoma (85), which refers to the rejection and regression of unirradiated metastatic lesions after the irradiation of a distant tumor location (86,87). More importantly, the addition of immunotherapy to radiotherapy can boost the abscopal effect (88) and, in turn, radiotherapy can enhance the effect of immunotherapy (89).…”

Irradiation immunity interactions

“…DNA damage responses to RT also results in interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) production by NK cells 41,42,73 and interleukin‐6 (IL‐6), IL‐12, TNF and IFN‐γ by TH type 1 (TH1) cells—typically aiding tumour cytotoxic immune responses 21,74 that boosts motility and tumour killing capacity of cytotoxic immune cells.…”

“…Radiation therapy can activate tissue repair mechanisms and chronic inflammation skewing TH cells from a type 1 phenotype (TH1) towards a TH type 2 phenotype (TH2)-typically associated with a pro-angiogenic, proinflammatory and immunosuppressive microenvironment favourable for tumour growth. 74,78 Tissue repair mechanisms and chronic inflammation also trigger macrophages to travel across the extracellular matrix (ECM) into the TME to clear dying/dead irradiated cancer cells. Here, they produce matrix metalloproteases (MMPs) that can facilitate cancer metastasis.…”