OS13.5.A INTEGRATIVE MULTIOMICS ANALYSIS IDENTIFIES TUMOR-ASSOCIATED MACROPHAGES AS NOVEL INDEPENDENT BIOMARKER FOR POOR SURVIVAL IN MENINGIOMAS

Abstract BACKGROUND Tumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies, but their role in the meningioma (MGM) microenvironment remains to be elucidated. MATERIAL AND METHODS Here, we investigated TAM frequencies, activation state, survival-associated changes, and their association with tumor-infiltrating T-lymphocytes (TILs) in two independent study samples comprising altogether 680 MGMs. To this end, we performed tissue cytometry analyses, quantified tissue cytokine levels, and integrated previously-published TIL infiltration and microarray datasets in the discovery cohort (n=195 clinically well-annotated cases). This was complemented by a DNA methylation-based deconvolution approach to predict TAM and TIL infiltration rates and survival associations in an independent validation cohort of n=485 MGMs. RESULTS Our findings revealed substantial but heterogeneous TAM infiltration in newly-diagnosed MGMs, with increased numbers of anti-inflammatory TAMs in clinically-aggressive tumors. Cytokine and transcriptome analyses corroborated the presence of an immunosuppressive niche in TAM-enriched MGMs. Importantly, high TAM infiltration was identified as an independent prognostic factor for poor survival, counteracting the beneficial prognostic effect of TILs. Furthermore, deconvolution analyses confirmed the opposing prognostic roles of TAMs and TILs in the validation cohort. CONCLUSION Methylation-based deconvolution to explore the prognostic impact of TAM and TIL composition in menigiomas may serve as a potential biomarker for immunotherapeutic treatment strategies. Furthermore, our findings highlight pro-tumoral TAMs to be an attractive treatment target in MGMs.