MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Michael Kilian, Ron Sheinin, Chin Leng Tan, Mirco Friedrich, Christopher Krämer, Ayelet Kaminitz, Khwab Sanghvi, Katharina Lindner, Yu Chan Chih, Frederik Cichon, Benjamin Richter, Stefanie Jung, Kristine Jähne, Miriam Ratliff, Robert M. Prins, Nima Etminan, Andreas von Deimling, Wolfgang Wick, Asaf Madi*, Lukas Bunse*Michael Platten*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.

Original languageEnglish
Pages (from-to)235-251.e9
JournalCancer Cell
Volume41
Issue number2
DOIs
StatePublished - 13 Feb 2023

Funding

FundersFunder number
Edmond J. Safra Center for Bioinformatics
Helmholtz International Graduate School for Cancer Research
University of Heidelberg Foundation
Israel Cancer Research Fund
Deutsches Krebsforschungszentrum
Deutsche Forschungsgemeinschaft404521405, PL315/10-1, SPP 2395, SFB 1389
Else Kröner-Fresenius-Stiftung2019_EKMS.49
Ministry of Science, ICT and Future Planning
Israel Cancer Association01028753
Israel Science Foundation1700/21
Tel Aviv University
Council for Higher Education
Dr. Rolf M. Schwiete StiftungCRC1366, PL-315/9-1, 39404578, 2021-009, RTG2727 - 445549683
Swiss Cancer Foundation
Dieter Morszeck Stiftung

    Keywords

    • CD8 T cell dysfunction
    • MHC class II
    • NFAT
    • TOX
    • glioblastoma
    • glioma
    • macrophages
    • microenvironment
    • myeloid cells
    • osteopontin

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