Tumor extracellular vesicles induce immunosuppressive myeloid cells via TIGIT/CD155 axis, dampening NLRP3-driven inflammatory response in glioblastoma 2257553
Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is marked by profound immune suppression. Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of this immunosuppressive environment. In this study, we examined the tumor-immune microenvironment using ultrasonic aspirate samples from GBM patients (n = 14). Several immune checkpoint molecules, including PDL1, B7-H3, and VISTA, were notably elevated. TIGIT, a receptor typically associated with T cells, was widely expressed across multiple myeloid subsets, including monocytic myeloid-derived suppressor cells (mMDSCs; 64.27±7.99%) and non-classical monocytes (NCM; 39.8±4.37%). Co-culture of healthy donor CD11b+ cells (n = 10) with TEVs replicated similar effects (mMDSCs; control 11.691.87 vs EV treated 23.322.0). We found CD155, a primary TIGIT ligand, to be heavily enriched in TEVs and co-localized with TIGIT in co-culture, suggesting the TIGIT/CD155 axis may be involved in promoting immune suppression. induced MDSCs markedly suppressed T cell proliferation (30.65 ± 5.97% vs. control 86.47 ± 2.94, p = 0.0001), accompanied by elevated Th2 cytokine production and increased NLRP3 and IL-1β expression. Interestingly, TIGIT knockdown did not affect NLRP3 expression, but did restore T cell proliferation (64.13±1.33%; p = 0.02) and pro-inflammatory cytokine production. However, this effect was lost upon NLRP3 knockdown, indicating its essential role in mediating immune rescue. Furthermore, IL-13 (a Th2 cytokine) blockade, in this model, enhanced pro-inflammatory response by suppressing phosphorylation of STAT-6 protein. Overall, our findings highlight a crucial role for the TIGIT/CD155 axis in driving myeloid-mediated immune suppression in GBM. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue. Neurosurgery Research & Education Foundation through the B*CURED & NREF Young Clinician Investigator Award, as well as intramural K12 funding through the Institute for Clinical and Translational Research and the NCI Paul Calabresi Career Development Award (1K12CA279871). Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)