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

Kilian, M.; Sheinin, R.; Tan, C. L.; Kraemer, C.; Friedrich, M.; Kaminitz, A.; Sanghvi, K.; Lindner, K.; Cichon, F.; Jung, S.; Jaehne, K.; Ratliff, M.; Prins, R.; von Deimling, A.; Wick, W.; Madi, A.; Bunse, L.; Platten, M.

doi:10.1101/2022.06.10.495502

bioRxiv · 10.1101/2022.06.10.495502

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

Kilian, M.·Sheinin, R.·Tan, C. L.·Kraemer, C.·Friedrich, M.·Kaminitz, A.·Sanghvi, K.·Lindner, K.·Cichon, F.·Jung, S.·Jaehne, K.·Ratliff, M.·Prins, R.·von Deimling, A.·Wick, W.·Madi, A.·Bunse, L.·Platten, M.

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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 (MHC) 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 nuclear factor of activated T cells (Nfat)2 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. Highlights- MHCII on intratumoral blood-borne myeloid cells is required for sustained anti-glioma T cell response - Loss of myeloid MHCII drives dysfunction of CD8+ T cells by activating TOX - Tox expression is induced by osteopontin-triggered chronic NFAT2 signaling in tumor-reactive CD8+ T cells - steopontin production is restricted upon intratumoral T helper cell activation via MHCII - MHCII expression on tumor-infiltrating bbm correlates with osteopontin expression and cytotoxic T cell dysfunction in human glioblastoma tissue O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/495502v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1fbedc7org.highwire.dtl.DTLVardef@b7dc3aorg.highwire.dtl.DTLVardef@db7fe6org.highwire.dtl.DTLVardef@aa06b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kilian, M., Sheinin, R., Tan, C. L., Kraemer, C., Friedrich, M., Kaminitz, A., Sanghvi, K., Lindner, K., Cichon, F., Jung, S., Jaehne, K., Ratliff, M., Prins, R., von Deimling, A., Wick, W., Madi, A., Bunse, L., Platten, M.. 2022-06-12. MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors. https://doi.org/10.1101/2022.06.10.495502

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