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

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 driver...

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Main Authors: Kilian, Michael (Author) , Sheinin, Ron (Author) , Tan, Chin Leng (Author) , Friedrich, Mirco (Author) , Krämer, Christopher (Author) , Kaminitz, Ayelet (Author) , Sanghvi, Khwab (Author) , Lindner, Katharina (Author) , Chih, Yu-Chan (Author) , Cichon, Frederik (Author) , Richter, Benjamin (Author) , Jung, Stefanie (Author) , Jähne, Kristine (Author) , Ratliff, Miriam (Author) , Prins, Robert M. (Author) , Etminan, Nima (Author) , Deimling, Andreas von (Author) , Wick, Wolfgang (Author) , Madi, Asaf (Author) , Bunse, Lukas (Author) , Platten, Michael (Author)
Format: Article (Journal)
Language:English
Published: 13 January 2023
In: Cancer cell
Year: 2023, Volume: 41, Issue: 2, Pages: 235-251
ISSN:1878-3686
DOI:10.1016/j.ccell.2022.12.007
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ccell.2022.12.007
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610822005931
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Author Notes: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, and Michael Platten

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245 1 0 |a MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors  |c 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, and Michael Platten 
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520 |a 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. 
650 4 |a CD8 T cell dysfunction 
650 4 |a glioblastoma 
650 4 |a glioma 
650 4 |a macrophages 
650 4 |a MHC class II 
650 4 |a microenvironment 
650 4 |a myeloid cells 
650 4 |a NFAT 
650 4 |a osteopontin 
650 4 |a TOX 
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