Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting behavior
Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), including the immune infiltrate. Here, we characterize the TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic and proteomic, including spatial single-cell approaches. Resolution of immune lineages indicates uniform high-infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoints, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M models tested. We show these myeloid populations communicate with H3-mutant cells mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoints showed significant therapeutic benefit in pre-clinical syngeneic models. Our findings provide valuable characterization of the TME of oncohistone-mutant gliomas, and insights into means to modulate the myeloid infiltrate for the benefit of patients. Overall design: 4 mouse tumor models of K27M pHGG generated by in-utero electroporation of mutations, sequenced for single-cell. These mutations include H3.3K27M, ATRX LOF, P53 LOF and PDGFRA WT overexpression (annotated as KAPP). 2 replicates of de-novo KAPP and 2 replicates of KAPP engrafted tumor; generated by engrafting the de-novo tumor in a new mouse.