The Reciprocity between Radiotherapy and Cancer Immunotherapy

Abstract

The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in the hope of producing synergistic antitumor responses. Radiotherapy, in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor micro-environment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design.

Ferroptosis, necroptosis, and pyroptosis in anticancer immunity

“…This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to the further investigation of combined-modality therapy for metastatic cancers. [162]. Hence, the combination of radiotherapy and immunotherapy is a promising modality for cancer treatment and is already supported by a well-designed clinical trial [163].…”

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“…Moreover, radiation activates antitumor immune responses by triggering the stimulator of interferon genes (STING)-mediated DNAsensing pathway, increasing infiltration of CD8+ T cells while reducing myeloid-derived suppressor cell accumulation, and upregulating the surface expression of PD-L1 on tumor cells. 29 On the other hand, immunotherapy may also sensitize tumors to radiation by promoting tumor blood vessel normalization, improving tissue perfusion, and decreasing intratumoral hypoxia. 30,31 It has been shown that the combination of immunotherapy and radiotherapy is well tolerated by most patients with solid cancers.…”

Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

“…The accumulation of mutant nucleic acid and proteins increases the odds of ICB treatment triggering tumor immunogenicity [ 84 , 85 ]. Besides modulating the release of antigens, the MHC molecules on tumor cells are also upregulated upon radiation, which activates the killing of T cells against tumors by binding to T cell receptors (TCRs) in the form of MHC-peptide transmitted by antigens presentation [ 86 , 87 ]. Furthermore, the irradiated tumor cells can also release DAMP and cytokines, which can enhance the translocation capacity of immune cells.…”

“…Radiation damage triggers the release of nuclear DNA into the cytosol, and cGAS can identify the mutant DNA in the cytoplasm and catalyzes the production of cGAMP, which serves as a second messenger to activate the ER membrane adaptor protein STING, which further stimulates TBK1 to activate the downstream transcription factors IRF3 and NF-κB. Subsequently, the expression of downstream type I interferon (IFN-I) is upregulated by the activated cGAS-STING axis through IRF3/NF-κB-dependent transcriptional activation ( Figure 2 ) [ 87 , 90 , 91 ].…”