Advancements in the research of immunomodulatory effects of radiation therapy: from basic to clinical

Abstract

Previously, radiotherapy was considered to directly kill tumor cells by deoxyribonucleic acid double-strand break. Recent studies have found that radiotherapy can also produce positive and effective anti-tumor effect by upregulating local and systemic immune responses. However, the immunomodulatory effect of radiotherapy is double-sided. On the one hand, it can activate anti-tumor immune-promoting effect, on the other hand, it may also produce immunosuppressive effect. The key molecular mechanisms of the positive regulation of adaptive and innate anti-tumor response by radiotherapy primarily include: induction of immunogenic cell death to promote the proliferation and activation of T lymphocytes; activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to induce type Ⅰ interferon response; changing the phenotype of tumor cells to enhance their immunogenicity and antigen visibility; stimulating tumor cells and stromal cells to release a variety of inflammatory factors and reshape the tumor immune microenvironment; upregulating the expression of immune checkpoint and death receptor on the surface of tumor cells to promote immune recognition and anti-tumor immune response. In addition, the mechanisms of negative immune suppression by radiotherapy mainly include: induction of tumor cells to upregulate the gene expression of multiple immunosuppressive factors; enhancing the function and effect of various immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells; leading to the decreased number of lymphocytes and the depletion of immunologic effector cells. Based on the above exploration of the mechanisms and principle of the immunomodulatory effect of radiotherapy, significant progress has also been shown in the clinical practice of combining radiotherapy with immunotherapy, such as the abscopal effect in the context of immunotherapy era, that is, the effective anti-tumor immune responses generated outside the irradiation field of radiotherapy, as well as the increased efficacy benefit when stereotactic body radiation therapy or low-dose radiotherapy combined with immune checkpoint inhibitors. However, at present, the synergistic mechanism of radiotherapy plus immunotherapy and its influencing factors are unclear. In the future, more in-depth investigations on optimal radiotherapy dose, segmentation regimens, irradiation sites and target volume design, immunotherapy agent selection and the sequence of combining radiotherapy with immunotherapy are necessary, in order to further improve efficacy and promote the translational application of immunomodulatory biological effects of radiotherapy. This article systematically reviewed the latest advancements of basic and clinical research on the immunomodulatory effect of radiotherapy and the synergy of combing radiotherapy with immunotherapy, aiming to provide guidance on the development of theoretical basis and clinical practice regarding the combination of radiotherapy and immunotherapy.

Keywords

• |radiotherapy|immunomodulatory|immune checkpoint inhibitor|abscopal effect