LAUSR

Gliomas are recalcitrant brain tumors. Differential tumor immune reactivity contributes to survival advantage of isocitrate dehydrogenase-mutant (IDHmut) over wild-type (IDHwt) gliomas. Despite this correlative pattern of immunity and survival, only a limited view of a highly complex immune contexture across IDH mutation classified gliomas is known. Herein, we present an unprecedented view of myeloid and lymphoid cell type diversity by single cell RNA sequencing and spectral cytometry-based interrogation of tumor-associated leukocytes from fifty-five IDH stratified primary and recurrent human gliomas and six non-glioma brains. Our analyses revealed twenty-two myeloid and lymphoid cell types within and across glioma subtypes. Glioma severity in relapsed IDHwt correlated with microglial attrition concomitant with a continuum of invading monocyte-derived microglia-like and macrophages amongst other infiltrating conventional T and NK lymphocytes and unconventional mucosa associated invariant T (MAIT) cells. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells (DCs). As tissue macrophages exhibit multifaceted polarization in response to microenvironmental cues, we clarify the existence of microglia/macrophage functional states beyond M1/M2 paradigms exemplified by the presence of palmitic-, oleic- acid, and glucocorticoid responsive polarized states. Immune related gene ontology analysis identified enriched antigen presentation and phagocytosis gene modules in distinct microglia-like clusters. Importantly, the phagocytic immunomodulator; Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) was upregulated in these microglia-like cells. Contrary to tumor promoting role of TREM2 myeloid cells in non-brain cancers, we identify TREM2 mediated anti-glioma axis as a regulator of antigen presentation Accelerated glioma growth was observed in Trem2 deficient mice implanted with CT2A glioma cells affirming the anti-glioma role of TREM2+ myeloid cells. In addition to providing an advanced landscape of glioma-specific immune contexture for immunotherapy applications, our reverse translational investigations discover TREM2 as a novel immunotherapy target for brain malignancies. Citation Format: Pravesh Gupta, Minghao Dang, Shivangi Oberai, Mekenzie Peshoff, Nancy Milam, Aml Ahmed, Krishna Bojja, Tuan M. Tran, Kathryn Cox, Huma Shehwana, Carlos Kamiya Matsuoka, Jianzhuo Li, Joy Gumin, Alicia Goldman, Sameer A. Seth, Atul Maheshwari, Frederick F. Lang, Nicholas E. Navin, Amy B. Heimberger, Karen Clise Dwyer, Linghua Wang, Krishna P. Bhat. Immunophenotyping of human brain tumors reveals myeloid cell mediated anti-glioma axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 669.