Year: 2025
Type: article
Abstract: Description Radiation therapy (RT) induces immunogenic cell death by releasing tumor antigens and endogenous adjuvants that activate the immune system. MyD88 signaling in myeloid cells restricts CD8+ T cell responses to RT in pancreatic cancer and we hypothesized that inflammasome activation occurs downstream of MyD88 post-RT. We observed increased levels of IL-1B and increased ASC-mCitrinebright monocytes and macrophages 24h post-RT, indicative of inflammasome activation. We identified P2X7R, glutathione, and mitochondrial ROS as critical mediators of inflammasome activation in macrophages responding to dying cancer cells post-RT. Caspase 1 inhibition significantly improved survival post-RT dependent on CD8+ T cells in male mice. Estrogen and progesterone inhibited inflammasome activation in co-cultures in vitro, while tamoxifen and mifepristone were required to restore the survival benefits of caspase-1 inhibition and RT in females. In males, Caspase-1 blockade led to a reduction in CD8+ T cell heterogeneity in the tumor draining LN, favoring expansion of a dominant activated effector phenotype marked by elevated expression of T-bet, Eomes, and Ki67. The functional implications of these findings were underscored by the increased antigen-specific CD8+ T cells intratumorally. These findings demonstrate that inflammasome activation in macrophages is a sex-dependent response that suppresses the immune response to RT and its blockade improves outcomes dependent on CD8+ T cells. Funding Sources Collins Medical Trust K22 CA251643 Providence Foundation Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Source: The Journal of Immunology
Institution: Mayo Clinic
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funder: National Institutes of Health
Awards: G5520316217, G9000038443
OpenAlex ID: W4416448762
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