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

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

doi:10.1016/j.ccell.2022.12.007

Cited by 48 publications

(30 citation statements)

References 83 publications

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“…However, anti-PD-1/PD-L1 immunotherapy has shown limited efficacy in most clinical studies of GBM (Yang et al, 2021). Pre-clinical models of glioma have demonstrated that CD4 + T cells are essential for tumor clearance and can induce tumor regression through therapeutic interventions without requiring CD8 + T cells (Chen et al, 2022;Kilian et al, 2022;Murphy et al, 2014;Murphy and Griffith, 2016). CD4 + T cells can also provide essential help to B cells for effective antibody-mediated immune responses (Eisenbarth et al, 2021;Gutierrez-Melo and Baumjohann, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, in murine colon adenocarcinoma and sarcomas, anti-tumor immunity relies on CD8 + T cell infiltration and effectively respond to anti-programmed cell death protein 1 (PD-1) immunotherapy (Binnewies et al, 2021;Molgora et al, 2020;Oh et al, 2018). In contrast, in brain tumors, recent studies have suggested that MHC class II-restricted CD4 + tumor-infiltrating lymphocytes (TILs) play a key role in regulating tumor clearance (Chen et al, 2022;Kilian et al, 2022). As a results, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), but not anti-PD-1, extended the survival of glioma mice in a CD4 + T cell-dependent manner (Chen et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, TREM2 deficiency reduced the immunosuppression of tumor-associated myeloid cells, suggesting that TREM2 can be detrimental in mouse models of peripheral tumors (Katzenelenbogen et al, 2020;Molgora et al, 2020;Timperi et al, 2022, Binnewies et al, 2021Zhang et al, 2022). To this end, we sought to investigate whether TREM2 is beneficial or detrimental in brain tumors.…”

Section: Introductionmentioning

confidence: 99%

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TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas

Zheng

Wang

Zhao

et al. 2023

Preprint

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Triggering receptor expressed on myeloid cells 2 (TREM2) was recently highlighted as a novel immune suppressive marker in peripheral tumors. The aim of this study was to characterize TREM2 expression in gliomas and investigate its contribution in glioma progression by using Trem2-/- mouse line. Our results showed that higher TREM2 expression was correlated with poor prognosis in glioma patients. Unexpectedly, TREM2 deficiency did not have a beneficial effect in a pre-clinical model of glioma. The increased TREM2 expression in glioma was likely due to increased myeloid cell infiltration, as evidenced by our single-cell analysis showing that almost all microglia and macrophages in gliomas were TREM2+. Furthermore, we found that deficiency of TREM2 impaired tumor-myeloid phagocytosis and MHCII presentation, and significantly reduced CD4+ T cells in tumor hemispheres. Our results revealed a previously unrecognized protective role of tumor-myeloid TREM2 in promoting MHCII-associated CD4+ T cell response against gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas

Zheng

Wang

Zhao

et al. 2023

Preprint

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“…Further, given our robust capture of diverse cell states, we were able to elaborate upon this concept, demonstrating through trajectory and maturity analyses that these precursors are not a static endpoint but instead give rise to other populations – including MHCII + hybrid TANs. While the role of MHCII + myeloid cells broadly in inducing T cell cytotoxicity has been established (Kilian et al, 2023), prior studies have dichotomized their origin into local and peripherally-derived. By contrast, our work defines skull marrow-derived cells as a third distinct lineage of intratumoral antigen presenting cells, not just in TANs but also in DCs and TAMs.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow

Lad

Beniwal

Jain

et al. 2023

Preprint

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Tumor-associated neutrophil (TAN) effects on glioblastoma biology remain under-characterized. We show here that 'hybrid' neutrophils with dendritic features - including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate MHCII-dependent T cell activation - accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this phenotype as a polarization state which is distinct from canonical cytotoxic TANs and differentiates intratumorally from immature precursors absent in circulation. Rather, these hybrid-inducible immature neutrophils - which we identified in patient and murine glioblastomas - arise from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a potent contributor of antitumoral myeloid APCs, including hybrid TANs and dendritic cells, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow - such as intracalvarial AMD3100 whose survival prolonging-effect in GBM we demonstrate - present therapeutic potential.

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“…We have recently published that functional activation of CD4 + T cells by glioma-infiltrating myeloid cells is a major determinant of CD8 + T cell fitness and prevents their differentiation into terminally exhausted T cells 40 . Additionally, we found this to be critical for responsiveness to immune checkpoint inhibition.…”

Section: Discussionmentioning

confidence: 99%

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

Boschert

Kromer

Lerner

et al. 2023

Preprint

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H3K27M, a driver mutation with T- and B-cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient who was treated with an H3K27M peptide vaccine and subsequently entered complete remission. The vaccine robustly expanded class II HLA-restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their CDR3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ, and -DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II-restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.

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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

Cited by 48 publications

References 83 publications

TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas

TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas

Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

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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

Cited by 48 publications

References 83 publications

TREM2 mediates MHCII-associated CD4+T cell response against gliomas

TREM2 mediates MHCII-associated CD4+T cell response against gliomas

Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

Contact Info

Product

Resources

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TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas

TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas