T-Cell Repertoire in Tumor Radiation: The Emerging Frontier as a Radiotherapy Biomarker

Abstract

Radiotherapy (RT) is a therapeutic modality that aims to eliminate malignant cells through the induction of DNA damage in the irradiated tumor site. In addition to its cytotoxic properties, RT also induces mechanisms that result in the promotion of antitumor immunity both locally within the irradiation field but also at distant tumor lesions, a phenomenon that is known as the “abscopal” effect. Because the immune system is capable of sensing the effects of RT, several treatment protocols have been assessing the synergistic role of radiotherapy combined with immunotherapy, collectively referred to as radioimmunotherapy. Herein, we discuss mechanistic insights underlying RT-based immunomodulation, which also enhance our understanding of how RT regulates antitumor T-cell-mediated immunity. Such knowledge is essential for the discovery of predictive biomarkers and for the improvement of clinical trials investigating the efficacy of radio-immunotherapeutic modalities in cancer patients.

Out-of-field effects: lessons learned from partial body exposure

“…In parallel, local radiotherapy, by inducing immunogenic cell death accompanied by increased release of danger signals activates pro-inflammatory mechanisms as well with immune stimulating outcome (Zhou et al 2021 ; Frey et al 2015 ; Baxevanis et al 2022 ; Brandmaier and Formenti 2020 ; Zhu et al 2021 ). Danger signals can activate professional antigen presenting cells, such as dendritic cells (DCs) (Lumniczky and Sáfrány 2015 ).…”

Radiotherapy-Related Gene Signature in Prostate Cancer

“…RT, in addition to its direct tumoricidal effects, additionally exerts indirect antitumor effects via systemic immune activation resulting in an active immunosurveillance against non-irradiated tumor cells. The immune-activating effects of the ionizing radiation are thought to be primarily mediated via the release of tumor antigens from the dying tumor cells which act as an in situ vaccine for tumor peptide-specific T-cell priming [ 11 ]. Other immunopotentiating effects of RT include, but are not restricted to, M1 macrophage and T-cell accumulation into the tumor as well as the release of immunostimulatory adjuvants locally, all of which support the combination of RT with immunotherapy [ 30 , 31 , 32 , 33 , 34 ].…”

“…Radiation therapy (RT) is an established treatment option for the management of localized PCa (LPCa) [ 5 ], which aims to directly kill tumor cells in the prostate gland and occasionally at distant anatomic sites [ 6 ]. There is accumulating evidence to suggest that RT generates local and also systemic immune-based pathways variously [ 7 , 8 ], but mostly via the release of tumor antigens which are specifically recognized by T cells and induce downstream signaling [ 9 , 10 , 11 ]. However, so far, there is no report on the identification of genes that are affected by RT and are involved in immune activation mechanisms controlling tumor progression.…”

Novel Drugs and Radiotherapy in Relapsed Lymphomas: Abscopal Response and Beyond

“…The cGAS-STING signaling is a master regulator for the production of type I IFNs within APC, which promotes the maturation and activation of APC and the expansion and survival of CD8+ T cells [7]. Besides releasing type I IFN, cGAS-STING also leads to the activation of the NF-κB signaling pathway, which stimulates APCs by the enhanced expression of IL-12 and CCR7, enhancing their tumor-associated antigens (TAAs) presented to lymphocytes, and priming immune system activity toward the antitumor response [8][9][10] (Figure 1). This change in the cytokine milieu and immune infiltration of the irradiated tissue is responsible for a reshaping effect of IR in the tumor-associated microenvironment (TAM), potentially shifting an immunologically "cold" disease to become a hot disease [11].…”