Radiation needs the inflammasome
The inflammasome is a multiprotein complex that is activated in response to pathogen and danger-associated molecular patterns, promoting inflammatory responses. Radiation therapy induces antitumor immune responses and inflammasome activation, yet how inflammasome activation contributes to antitumor immunity is unclear. Here, Han et al. used knockout mouse models to show that the AIM2 and NRLP3 inflammasomes were both needed for radiation-induced antitumor immunity. These inflammasomes induced IL-1β maturation, which activated dendritic cells in an IL-1R–mediated manner, leading to T cell activation and antitumor immunity. Local IL-1β treatment reversed the radioresistance of a mouse tumor model. Together, these data suggest a role of the inflammasome in radiation-induced antitumor immunity and show that local IL-1β treatment can be used to overcome radioresistance.
Abstract
The inflammasome promotes inflammation-associated diseases, including cancer, and contributes to the radiation-induced tissue damage. However, the role of inflammasome in radiation-induced antitumor effects is unclear. We observed that tumors transplanted in Casp1−/− mice were resistant to radiation treatment compared with tumors in wild-type (WT) mice. To map out which molecule in the inflammasome pathway contributed to this resistant, we investigated the antitumor effect of radiation in several inflammasome-deficient mice. Tumors grown in either Aim2−/− or Nlrp3−/− mice remained sensitive to radiation, like WT mice, whereas Aim2−/−Nlrp3−/− mice showed radioresistance. Mechanistically, extracellular vesicles (EVs) and EV-free supernatant derived from irradiated tumors activated both Aim2 and Nlrp3 inflammasomes in macrophages, leading to the production of interleukin-1β (IL-1β). IL-1β treatment helped overcome the radioresistance of tumors growing in Casp1−/− and Aim2−/−Nlrp3−/− mice. IL-1 signaling in dendritic cells (DCs) promoted radiation-induced antitumor immunity by enhancing the cross-priming activity of DCs. Overall, we demonstrated that radiation-induced activation of the AIM2 and NLRP3 inflammasomes coordinate to induce some of the antitumor effects of radiation by triggering IL-1 signaling in DCs, leading to their activation and cross-priming.
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