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Radiation therapy can induce DNA damage in tumor cells and promote tumor cell death. Dead tumor cells can further modulate innate immune pathways in the tumor microenvironment, thereby modulating anti-tumor adaptive immune responses. The inflammasome pathway, as an important innate immune response barrier against exogenous microbial infection, can recognize and respond to different stimuli through a variety of inflammasome pattern receptors. Among them, the AIM2 inflammasome (Nature | "Life is about to die" - AIM2 inflammasome simultaneously promotes the proliferation and pyroptosis of macrophages leading to atherosclerosis ; Nature | AIM2 inflammasomes monitor DNA Injury to affect nervous system development) responds to dsDNA aggregated in the cytoplasm, and NLRP3 can more broadly recognize a variety of extracellular and intracellular stimuli, which in turn promotes two pro-inflammatory factors by activating Caspase 1 (CASP1) (IL-1β and IL-18) Activation and release of and promotion of pyroptosis. So far, the regulatory role of inflammasome on in tumor radiotherapy has not been reported. It is worth mentioning that the previous research results of Professor Fu Yangxin 's team showed that radiotherapy can promote the aggregation of dsDNA in dendritic cells , thereby activating the cGAS-STING signaling pathway-mediated type I interferon production, and then Promote radiotherapy-induced anti-tumor immune response (See BioArt report: Nat Immuno | Fu Yangxin's team revealed that tumor cells inhibit radiotherapy and immunotherapy ) by hijacking the CASP9 signaling pathway. The CASP1-mediated inflammasome pathway was found to inhibit the activation of cGAS-STING signaling during the virus, thereby reducing the antiviral effect mediated by type I interferon.Therefore, the effect of CASP1-mediated inflammasome and cGAS-STING pathway on radiotherapy in tumors needs to be further studied.
2021年5月7日，美国德克萨斯大学西南医学中心的傅阳心团队和Hasan Zaki在Science Immunology上发表题为The AIM2 and NLRP3 inflammasomes trigger IL-1–mediated antitumor effects during radiation 研究Paper (first author Dr. Han Chuanhui , Victoria Godfrey1) . The research paper further analyzed the inflammasome-mediated IL-1 antitumor pathway in radiotherapy.
The authors first found that tumor cells proliferated slowly in Casp1-/- mice; however, tumor cells in Casp1-/- mice showed significant resistance to radiotherapy compared to WT mice. This suggests that the CASP1-mediated inflammasome pathway is crucial for radiotherapy. Given the inhibitory effect of CASP1 on the cGAS-STING pathway, this suggests that the regulation of the CASP1-mediated inflammasome pathway on radiotherapy is independent of the activation of the cGAS-STING pathway. Unlike in Casp1-/- mice, however, the authors found that tumor cells in Aim2-/- and Nlrp3-/- mice responded well to radiation therapy, similar to wild-type mice. This indicates that the activation of CASP1 does not depend on the AIM2 or NLRP3 single inflammasome pathway.Further mechanistic studies have shown that after radiation treatment, tumor cells can induce the activation of AIM2 inflammasome by secreting extracellular vesicle (EV) , and EV-free components can activate the NLRP3 inflammasome pathway, thereby Together they promote the production of IL-1β.
To reveal the effects of AIM2 and NLRP3 inflammasomes on radiotherapy, the authors further constructed Aim2-/--Nlrp3-/- mice. The authors found that tumor cells were resistant to radiation in Aim2-/--Nlrp3-/- mice, similar to -/- mice. This suggests that radiation treatment activates both AIM2 and NLRP3 inflammasomes, thereby promoting the activation of CASP1. The authors then conducted an in-depth analysis of the downstream molecules of CASP1 and found that the loss of the IL-18 signaling pathway did not affect the efficacy of radiotherapy, while the loss of the IL-1 signaling pathway resulted in tumor cells being resistant to radiotherapy. This indicates that radiotherapy can promote tumor killing by activating the AIM2/NRLP3-CASP1-IL-1 signaling pathway.
In order to analyze the mechanism of IL-1, the authors constructed conditional deletion mice of IL-1R1 in T cells , macrophages and dendritic cells. The results showed that the specific deletion of IL-1R1 on T cells and dendritic cells did not affect the control effect of radiotherapy; whereas the deletion of IL-1R1 in dendritic cells made tumor cells resistant to radiotherapy treatment. This indicates that the IL-1 signaling pathway of dendritic cells can promote the therapeutic effect of radiotherapy. Dendritic cells, as the most important antigen presenting cells in the body, can regulate the proliferation and activation of CD8+T through cross-priming.Previous studies have shown that radiotherapy relies on pre-existing CD8+ T cells in tumor tissue rather than CD8+ T cells recruited after radiotherapy. However, the mechanism of how Pre-existing CD8+ T cells antagonize death and maintain antitumor effect after high-dose radiation treatment remains unknown. Therefore, the authors further explored the regulatory role of dendritic cell IL-1 signaling pathway on CD8+T after radiation treatment. The authors found that, when co-incubated with CD8+ T cells, Il1r1-/- dendritic cells had significantly reduced activation of radiation-treated CD8+ T cells compared to wild-type dendritic cells, and surviving CD8+ The number of T cells was also significantly reduced. In vivo experiments also showed that the number of pre-existing CD8+ T cells in tumor tissues of Il1r1-/- mice was significantly reduced after radiation treatment. This indicates that the dendritic cell IL-1 signaling pathway can promote the survival and function of CD8+ T cells after radiation treatment through the function of cross-priming. The authors further found that intratumoral injection of IL-1β could not only overcome the antagonism of tumor cells to radiotherapy in Casp1-/- and Aim2-/--Nlrp3-/- mice, but also significantly increased tumor cell resistance in WT mice. Sensitivity to radiotherapy. However, in Il1r1-/- mice and dendritic cells IL-1R1 conditionally deleted mice, IL-1β was not able to synergize with radiotherapy. This further illustrates the important regulatory role of dendritic cell IL-1 signaling pathway on radiotherapy. This work revealed for the first time the important role of dendritic cell IL-1 signaling pathway in the survival and function of CD8+T after radiotherapy, thus putting forward a new focus for clinical treatment: how to maintain pre-existing CD8+T after radiotherapy survival and activation.
It is worth mentioning that Dr. Han Chuanhui of Fu Yangxin’s team published a preliminary study in Nature Immunology, revealing that tumor cells can hijack the CASP9 signaling pathway to inhibit radiotherapy and immunotherapy. The therapeutic strategy of immunotherapy (see BioArt's previous article "Nat Immuno | Fu Yangxin's team reveals that tumor cells inhibit radiotherapy and immunotherapy by hijacking the CASP9 signaling pathway") . However, as a broad-spectrum inhibitor of Caspases, Emricasan can not only inhibit CASP9/8/3/7-mediated apoptosis of cells , but also inhibit CASP1-mediated inflammasome signaling pathway. This work also pointed out the disadvantages of Emricasan in the synergistic effect of radiotherapy and immunotherapy, and provided important basic support for the research of Caspases inhibitor in tumor treatment, and further improved the synergistic treatment strategy of Emricasan and tumor radiotherapy. indicated the way. Therefore, how to circumvent the inhibitory effect of Caspases inhibitors on the inflammasome is worthy of further study.
The corresponding authors of the paper are Prof. Fu Yangxin and Prof. Hasan.Zaki from the University of Texas Southwestern Medical Center, and Dr. Han Chuanhui and Victoria.GoodFrey are the co-first authors of the paper.
Original link:
http://immunology.sciencemag.org/lookup/doi/10.1126/sciimmunol.abc6998
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