Inflammasome activation in macrophages limits CD8+ T cell response to radiotherapy

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B102
Abstract ID: 5776

Presenting Author:
Sina Ramin , Research Fellow at Earle A. Chiles Res. Inst., Providence Cancer Inst.

Abstract:

Radiation therapy (RT) induces immunogenic cell death by releasing tumor antigens and endogenous adjuvants that activate the immune system. We previously reported that MyD88 signaling in myeloid cells restricts CD8+ T cell responses to RT in pancreatic cancer and hypothesized that inflammasome activation occurred downstream of MyD88 post-RT.  We observed increased levels of IL-1b and increased ASC-mCitrine^bright monocytes and macrophages 24h post-RT. Mechanistically, activation of the NLRP3 inflammasome occurs in macrophages downstream of mitochondrial ROS production. Inhibition of caspase 1 in vivo significantly improved survival post-RT dependent on CD8+ T cells, but only in male mice. We found that estrogen and progesterone inhibited inflammasome activation in response to RT, revealing a sex-specific impact on the inflammasome. In males, Caspase-1 blockade led to a reduction in CD8+ T cell heterogeneity in the tumor draining LN, favoring the 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 suppresses the immune response to RT and its blockade improves outcomes dependent on CD8+ T cell responses.