Han et al. observed that, relative to WT, casp1 knockout mice were resistant to tumor irradiation therapy. They examined individual components of this CASP1-dependent (IL-1-dependent) response to tumor irradiation by utilizing an array of gene- and cell type-specific knockout and Cre recombinase transgenic mice. Extracellular vesicular components of irradiated tumors activated the AIM2 inflammasome, and tumor supernatant induced IL-1 production through NLRP3. These two pathways coordinated in the production of IL-1, resulting in DC activation and cross-priming of intratumoral CD8+ T cells.
Contributed by Margot O’Toole
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.
Author Info: (1) Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. (2) Institute of Biophysics, Chinese Academy of Sciences. Beijing, China. (3) Department of Radiation
Author Info: (1) Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. (2) Institute of Biophysics, Chinese Academy of Sciences. Beijing, China. (3) Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA. (4) Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. hasan.zaki@utsouthwestern.edu yang-xin.fu@utsouthwestern.edu.
