Tumor-Associated Macrophages in Meningiomas: An Independent Prognostic Factor for Poor Survival Outperforming the Benefits of T cells

Abstract

BackgroundTumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies. To elucidate their biological impact in the tumor microenvironment (TME) of meningiomas (MGMs), we assessed TAM numbers, activation state, malignancy- and survival-associated changes, as well as their association with tumor-infiltrating T lymphocytes (TILs). MethodsTAM infiltration was analyzed in a multicenter cohort of 195 clinically well-annotated cases (follow-up >5 years, n=120 newly-diagnosed and n=75 recurrent MGMs) enriched for higher-grade MGMs. TAMs and M2-TAMs were quantified by tissue cytometry on whole-tumor sections. Further, we assessed levels of 27 cyto- and chemokines in a subset of tissues (n=46 cases), and re-analyzed our previously published T cell infiltration (n=94 cases) and expanded microarray (n=97 cases) datasets. ResultsNewly-diagnosed MGMs showed a substantial but highly heterogeneous TAM infiltration that was four times higher than for TILs. Anti-inflammatory M2-TAMs were increased in higher WHO grade tumors and in recurrent MGMs. Importantly, high M2-TAM infiltration was associated with poor progression-free survival independent of other prognostic confounders and even mitigated the beneficial prognostic effect of TIL infiltration. Additional cytokine, gene expression and pathway analyses corroborated the presence of an immunosuppressive niche in M2-TAM-enriched MGMs. ConclusionsAltogether, higher numbers of TAMs and M2-TAMs appear to be a hallmark of clinically aggressive behavior in newly-diagnosed and recurrent MGMs. Unlike TILs, immunosuppressive TAMs seem to play a dominant negative role in the immunological landscape of MGMs, highlighting M2-TAMs to be an attractive treatment target for immunotherapeutic approaches. Translational Relevance of the StudyMeningiomas (MGMs) are typically regarded as benign neoplasms, however there is a substantial proportion of clinically aggressive tumors that are refractory to standard treatment modalities and demand for the development of novel therapeutic approaches such as immunotherapy. This is the first comprehensive study reporting malignancy- and progression-associated changes of tumor-associated macrophages (TAMs), their polarization state, their association with tumor-infiltrating T lymphocytes (TILs), and their impact on patient survival in a large multicenter cohort of 195 tumors containing substantial numbers of clinically aggressive cases. Notably, we identified higher numbers of immunosuppressive M2-TAMs as an independent prognostic factor for poor survival, overriding the beneficial prognostic effects of TILs. Thus, our data highlight an important role of immunosuppressive M2-TAMs on tumor malignancy and progression, and further suggest targeting macrophages as a treatment strategy to improve the success of immunotherapeutic approaches in MGMs. Key pointsO_LIMeningiomas are highly infiltrated by immunosuppressive M2-TAMs. C_LIO_LIHigh M2-TAM numbers are an independent negative prognostic factor for patient survival. C_LIO_LIHigh TAM infiltration mitigates the beneficial prognostic impact of TILs. C_LI