Postdoctoral Fellow Providence cancer institute, Oregon, United States
Disclosure(s):
Sina Ramin, MD: No financial relationships to disclose
Introduction/Rationale: Radiation therapy (RT) induces immunogenic cell death and antitumor immunity. We demonstrated that myeloid MyD88 signaling restricts CD8⁺ T cell responses after RT and hypothesized that inflammasome activation downstream of MyD88 contributed to this phenotype.
Methods: We cocultured bone marrow–derived macrophages and PK5L1940 pancreatic tumor cells in the presence of specific inhibitors to assess the mechanism of inflammasome activation following RT. WT or ASC-mCitrine reporter mice bearing subcutaneous tumors were treated with RT and the caspase-1 inhibitor VX765, with immune profiling and inflammasome activity assessed by flow cytometry.
Results: RT activated the NLRP3 inflammasome in macrophages dependent on ER Ca2+ release, and mitochondrial ROS. VX765 improved post-RT survival in a CD8⁺ T cell–dependent manner, with efficacy observed in males. VX765 enhanced the expansion of T-bet⁺Eomes⁺Ki67⁺ CD8⁺ effector cells and increased tumor antigen–specific T cells. RT also induced IL-23 expression and Th17 response, while VX765 further upregulated IL-23R expression on CD4⁺ T cells. In females, estrogen and progesterone suppressed inflammasome activation, and VX765 efficacy required hormonal blockade.
Conclusion: NLRP3 inflammasome activation limits RT-induced antitumor immunity by restricting CD8⁺ responses. VX765 enhances effector CD8+ T cell expansion and survival in males post-RT. Sex hormones modulate inflammasome activity, impacting efficacy of its blockade in combination with RT.
