Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function
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), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse 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 checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.
Authors
- Jason Karamchandani (ORCID: https://orcid.org/0000-0002-3906-5616)
- Michele Zeinieh (ORCID: https://orcid.org/0000-0002-0875-2077)
- Daniela F. Quail (ORCID: https://orcid.org/0000-0002-6969-3250)
- Dhana Llivichuzhca-Loja
- Geoffroy Danieau (ORCID: https://orcid.org/0000-0003-1491-9221)
- Evan Puligandla (ORCID: https://orcid.org/0000-0001-8449-9221)
- Alva Annett (ORCID: https://orcid.org/0000-0002-3258-4296)
- Caterina Russo (ORCID: https://orcid.org/0000-0002-7770-0457)
- Emily M. Nakada
- Claudia L. Kleinman (ORCID: https://orcid.org/0000-0002-5158-7126)
- Elham Karimi (ORCID: https://orcid.org/0000-0002-2204-0789)
- Danai G. Topouza (ORCID: https://orcid.org/0000-0002-6897-9281)
- Damien Faury (ORCID: https://orcid.org/0000-0003-1584-599X)
- Benjamin Ellezam (ORCID: https://orcid.org/0000-0002-8716-7924)
- Eduardo Gonzalez Santiago (ORCID: https://orcid.org/0009-0007-0330-7947)
- Valérie Larouche (ORCID: https://orcid.org/0000-0003-4082-7267)
- Liza Konnikova (ORCID: https://orcid.org/0000-0003-4804-5497)
- Sameer Agnihotri (ORCID: https://orcid.org/0000-0001-6584-3795)
- Nikoleta Juretic (ORCID: https://orcid.org/0000-0001-8265-8305)
- Y. Lucy Liu
- Michael McNicholas (ORCID: https://orcid.org/0000-0002-6920-9924)
- Antonella De Cola (ORCID: https://orcid.org/0000-0002-3202-5339)
- Selin Jessa (ORCID: https://orcid.org/0000-0003-4192-6523)
- Nada Jabado (ORCID: https://orcid.org/0000-0003-2485-3692)
- Brian Krug (ORCID: https://orcid.org/0000-0003-3037-7143)
- Manav Pathania (ORCID: https://orcid.org/0000-0001-5635-5028)
- Steven Hébert (ORCID: https://orcid.org/0000-0001-6267-8595)
- Roy Dudley (ORCID: https://orcid.org/0000-0003-4437-0823)
- Alexander G. Weil (ORCID: https://orcid.org/0000-0003-4162-6096)
- Logan A. Walsh (ORCID: https://orcid.org/0000-0001-8771-2577)
- Morteza Rezanejad (ORCID: https://orcid.org/0000-0001-8744-8534)
- Arne Gehlhaar (ORCID: https://orcid.org/0000-0001-8120-4942)
- Augusto Faria Andrade (ORCID: https://orcid.org/0000-0001-5866-0501)
- Bhavyaa Chandarana (ORCID: https://orcid.org/0009-0002-7972-2892)
- Qing Wu (ORCID: https://orcid.org/0000-0002-8252-2990)
- Yuhong Wei
Institutions
- Montreal Neurological Institute and Hospital (CA)
- University of Bonn (DE)
- University of Pittsburgh (US)
- University of Toronto (CA)
- Montreal Children's Hospital (CA)
- McGill University Health Centre (CA)
- Jewish General Hospital (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Yale University (US)
- Brain Tumour Research (GB)
- McGill Genome Centre (CA)
- Jenner Institute (GB)
- Neurological Surgery (US)
- MRC Epidemiology Unit (GB)
- Life & Brain (Germany) (DE)
- Université Laval (CA)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1038/s41467-024-52096-w
- Citations
- 25
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 6.01
Funders
- Yale University
- McGill University
- Genome Canada
- Cancer Research Society
- Génome Québec
- Brain Research UK
- Government of Ontario
- McGill University Health Centre
- Government of Canada
- Cancer Research UK
- Great Ormond Street Hospital Charity
- Jewish General Hospital
- Fondation Charles-Bruneau
- Alliance de recherche numérique du Canada
- National Institutes of Health
- Stand Up To Cancer
- Canadian Institutes of Health Research
- Canadian Cancer Society Research Institute
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé