IMMU-24. CHEK2 haploinsufficiency drives immune responsiveness in aggressive meningiomas

Abstract Meningiomas account for more than 30% of all primary central nervous system (CNS) tumors. Although approximately 80% of meningiomas are benign (WHO Grade 1), the remaining 20%, which include Grade 2 and 3 tumors, exhibit poor progression-free survival and resistance to radiotherapy, chemotherapy, and immune checkpoint blockade (ICB) therapy. The lack of therapeutic response in molecularly unselected meningiomas highlights the need for targeted treatment strategies. Loss of heterozygosity (LOH) at the Chromosome 22q12.1 locus is a hallmark of aggressive meningiomas, occurring in over 63% of high-grade cases. The Checkpoint Kinase 2 (CHEK2) gene, located on Chr22q12.1, is frequently co-deleted with NF2 in more than 60% of high-grade meningiomas. Our previous work in gliomas demonstrated that genetic depletion or pharmacological inhibition of CHEK2 synergizes with ICB therapy. Based on this, we hypothesized that CHEK2 haploinsufficiency renders meningiomas more immune inflammatory. In two previously reported meningioma cohorts (n=584), the immune-enriched methylation subgroup showed significantly lower CHEK2 expression relative to the hypermitotic and merlin-intact subgroups. Knockout or kinase activity inhibition of CHEK2 in both human and murine meningioma cells led to enhanced antigen presentation, STING pathway activation, increased type I interferon response and PD-L1 upregulation. Moreover, transcriptomic analyses of human meningiomas revealed an inverse association between CHEK2 expression and markers of lymphocyte activation and proliferation. These findings identify CHEK2 haploinsufficient meningiomas as an immune-activated subgroup and provides rationale for their selection as candidates for ICB therapy.