Mohammad, Asad

Abstract Description Glioblastoma (GBM), the most common and deadly primary brain tumor in adults, is associated with profound local and systemic immune suppression. Increasing evidence points to tumor-derived extracellular vesicles (EVs) as key mediators of this immunosuppression. In surveying the tumor-immune microenvironment in samples of ultrasonic aspirate collected during surgical resection of GBM (n = 12), we identified several key immunomodulatory markers expressed across a range of immune cells in the tumor microenvironment. Particularly, we found TIGIT, classically understood as a T cell inhibitory protein, expressed across a range of myeloid cell populations, including in myeloid-derived suppressor cells (MDSCs, 46.84±16.78% of total monocytic MDSCs). Co-culture of healthy donor monocytes (n = 10) with patient-derived EVs replicated similar effects (control 11.69±1.87 vs EV treated 23.32±2.0). Furthermore, Induced MDSCs significantly inhibit T cell proliferation (30.65±5.97% proliferation, v/s control 86.47±2.94, p = 0.0001), concomitant with a surge in Th2 immune responses via TIGIT+ suppressive monocytes. Targeted TIGIT inhibition restored T cell proliferation (64.13±1.327% v/s non-inhibited, 30.65±5.97%; p = 0.02) and protective immune response, confirming a pivotal role of TIGIT in immune suppressive GBM microenvironment. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue. Funding Sources Neurosurgery Research& Education Foundation, K12 grant Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)