Blood-Borne Myeloid Cell Loss of MHCII Drives Cytotoxic T-cell Dysfunction

Response to cancer immunotherapies is dependent on the infiltration and function of cytotoxic CD8⁺ T cells, with dysfunctional cytotoxic T cells being a major contributor to immune checkpoint inhibitor (ICI) resistance in patients with glioblastoma. Previous studies have shown that intratumoral myeloid cells, especially blood-borne myeloids (bbm), drive this T-cell dysfunction in the tumor microenvironment, but the role of these bbms in controlling brain tumor growth has not been fully elucidated. Kilian, Sheinin, and colleagues sought to determine the impact and underlying mechanisms of these bbm cells along with major histocompatibility complex II (MHCII)–restricted antigen presentation to brain tumor immunosurveillance and showed that MHCII on bbm cells, but not brain-resident microglia, is needed for continued tumor-reactive CD8⁺ T-cell responses as well as response to ICIs. Loss of myeloid MHCII led to the reduced tumor killing capacity of cytotoxic CD8⁺ T cells, and evaluation of the transcriptional programs in these T cells indicated an induction of a TOX-regulated exhaustive state, leading to T-cell dysfunction. Moreover, loss of MHCII on bbm cells led to the upregulation of osteopontin (OPN) in bbm cells, which induces Tox expression in activated CD8⁺ T cells through the promotion of chronic NFAT2 signaling. Investigation into MHCII regulation of OPN expression revealed that CD4⁺ T cells, activated by antigen-presenting bbm cells through MHCII, release IFNγ to suppress OPN expression in bbm cells, while loss of myeloid MHCII prevents CD4⁺ T-cell activation, resulting in sustained OPN production and a dysfunctional CD8⁺ T-cell state. In line with this, expression of MHCII on bbm cells was negatively correlated with the exhausted CD8⁺ T-cell dysfunctional state in human glioma tissue. In summary, this study provides a mechanism behind the functional control of cytotoxic CD8⁺ T-cell function in brain tumors through intratumoral MHCII-restricted antigen presentation on bbm cells as well as reveals potential targets for the rational design of immunotherapies.

Kilian M, Sheinin R, Tan CL, Friedrich M, Krämer C, Kaminitz A, et al. MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors. Cancer Cell 2023;41:235–51.

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