TMIC-78. CIRCADIAN REGULATOR CLOCK DRIVES IMMUNOSUPPRESSION IN GLIOBLASTOMA

Abstract The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for progression. However, molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) its heterodimeric partner brain muscle ARNT-like 1 (BMAL1) glioma (GSCs) drive immunosuppression GBM. Integrated analyses of data from transcriptome profiling, single-cell RNA sequencing, TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target CLOCK–BMAL1 complex GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN GSCs via hypoxia-inducible factor 1-alpha (HIF1A) signaling. Consequently, promotes microglial infiltration into GBM TME upregulating CD162, polarizes infiltrating microglia towards an immune-suppressive phenotype. In mouse models, inhibition CLOCK–OLFML3–HIF1A–LGMN–CD162 axis reduces intratumoral microglia, increases CD8+ T cell infiltration, activation cytotoxicity, synergizes anti-PD1 therapy. human GBM, CLOCK-regulated signaling correlates positively level poor prognosis. Together, these findings uncover CLOCK–OLFML3–HIF1A–LGMN switch controls biology immunosuppression, thus revealing potential new therapeutic targets patients.