Work

Conditional knockouts demonstrate that the autoimmune-associated nuclease DNAse1L3 regulates tumor control by radiation therapy in preclinical models 3234

Year: 2025

Type: article

Abstract: Description After radiation therapy, cancer cells release microparticles and apoptotic bodies containing various antigenic targets and immunogenic adjuvants, like DNA, into the tumor microenvironment. Immunostimulatory DNA can be cleaved by DNAse1L3, which is secreted by macrophages and dendritic cells in the tumor microenvironment. DNAse1L3 exhibits greater efficiency than DNAse1 in the internucleosomal cleavage of genomic DNA, and its loss drives autoimmunity. Therefore, we hypothesized that loss of myeloid Dnase1L3 production would enhance the response to radiation therapy. We crossed Dnase1L3fl/fl mice with CMV-Cre, LysM-Cre, or CD11c-Cre mice, and challenged them with panel of tumor models. Surprisingly, loss of Dnase1L3 impaired tumor control by CT-guided radiation. Using multispectral flow cytometry, we demonstrate that loss of Dnase1L3 altered DC and T cell maturation in the tumor and tumor-draining lymph nodes compared to wild-type mice. Finally, using bone marrow-derived macrophages, we demonstrate that the expression of the Dnase1L3 gene is tightly regulated by various TLR and STING ligands that may impact Dnase1L3 expression in the tumor following radiation therapy. Altogether, our findings underscore a previously unrecognized role for this gene in tumor control and elucidate its regulation in the post-radiation tumor immune environment. Funding Sources Supported by NIH R21 CA277250 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1054