IMMU-58. Integrated multiomic profiling identifies genomic and immune microenvironmental changes as candidate resistance mechanisms to PD-1 blockade in high-grade meningiomas

Abstract High-grade meningiomas (HGMs) are aggressive tumors with limited systemic treatment options and poor long-term survival. A recent phase 2 trial (NCT03279692) of pembrolizumab demonstrated clinical benefit in a subset of HGMs (Brastianos et al. Nature Communications 2022), highlighting the need to identify biomarkers of response. To address this, we performed genomic and immune profiling of tumor and plasma samples from 25 patients treated with pembrolizumab as part of this trial. Homozygous deletion of CDKN2A and loss of chromosome arm 9p were significantly enriched in non-responders and associated with worse progression-free survival (PFS; HR 6.15 and 14.95, respectively; p < 0.05) and overall survival (OS; HR 6.3 and 4.32, respectively; p < 0.05). Among these, 9p loss emerged as the strongest predictor of poor PFS and genes lost on 9p were significantly enriched for immune-related functions (p < 0.05), suggesting an additional role for 9p loss beyond focal CDKN2A deletion alone, in driving immune evasion and resistance to PD-1 blockade. Multiplexed immunofluorescence profiling revealed higher tumor proliferation (Ki67⁺) in non-responders, while responders showed greater infiltration of CD3e⁺, CD20⁺, FOXP3⁺ cells and higher PD-1/PD-L1 expression (all p < 0.05). CD68⁺ macrophages and CD8⁺ T cells increased post-treatment, with responders enriched for proliferative B cells and PD-1⁺/PD-L1⁺ cells (p < 0.05). Responders also showed more CD20-PD1 and CD163-PD1 interactions (p < 0.05). CDKN2A-mutant tumors, including those with co-occurring 9p loss, exhibited higher Ki67⁺ and depleted CD20⁺, FOXP3⁺, CD4⁺, and PD-1⁺ cells, with reduced immune interactions (all p < 0.05). Our findings suggest that loss of chromosome 9p, in combination with CDKN2A deletion, defines a hyperproliferative, immune-cold subset of HGMs that are resistant to PD-1 blockade, nominating 9p loss as a potential biomarker of immunotherapy resistance and a candidate driver of immune exclusion.