Single cell mapping of human brain tumors reveals tumor-specific education of tissue-invading leukocytes.

Abstract

2509 Background: Brain tumors can be both of intracranial origin (e.g. gliomas) or spread from another location in the body (metastases). Tumor growth in the CNS is commonly favored by a highly immunosuppressive tumor microenvironment (TME). Whether the TME is predominantly shaped by the CNS microenvironment or by the nature of the malignancy is unknown, as is the origin and function of CNS tumor-associated macrophages (TAM). Methods: We have mapped the leukocyte landscape of brain tumors using high-dimensional profiling with mass cytometry (CyTOF). We designed two CyTOF panels (one lymphoid and one myeloid focused) measuring 74 parameters at the single-cell level and analyzed samples from 47 individuals with the most common tumor entities being glioblastoma and metastases from melanoma and lung cancer as well as control tissue from epilepsy surgery. Results: The heterogeneous composition of tissue-resident and invading immune cells within the TME alone permitted a clear distinction between glioblastoma and metastases. Tissue-invading leukocytes accumulate in metastases, whereas gliomas predominantly contain tissue-resident reactive microglia. In gliomas, isocitrate dehydrogenase 1 (IDH1) mutations are associated with minimal host responses whereas IDH1-wildtype gliomas comprise monocyte-derived macrophages (MDM) similar to metastases. These MDM show a distinctive signature trajectory indicative of tumor-driven education. Conclusions: The immune cell composition of the brain tumor TME is tumor entity-specific, rather than dictated by the CNS tissue. Defining the distinct immunological signature of brain tumors can facilitate the rational design of targeted immunotherapy strategies.