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Abstract
Background Gliomas are the most prevalent type of brain tumors in the adolescent and young adult population (AYA) and one of the leading causes of cancer- related death.1 Low-grade gliomas are more frequent, but there are no specific treatments to prevent the malignant transformation (MT) into high-grade glioma (HGG) in AYA. Current glioma therapies failed to arrest the MT due to innate resistance mechanisms within the brain tumor microenvironment (TME), associated with a robust infiltration of bone marrow-derived myeloid cells (BMDMs).2 These BMDMs are myeloid precursors that migrate to the tumor site, attracted by cancer-related inflammatory cytokines, and differentiate into pro-tumoral immunosuppressive myeloid cells (MDSCs and TAMs).3 Our previous study in vivo demonstrated upregulation of CD74 in immunosuppressive myeloid cells, and its impact on the survival of glioma patients.4 CD74 is a transmembrane MHC-class II chaperone and binding with MIF triggers activation of the intracellular pathway, leading to gene expression regulation of immunoregulatory molecules.5 We hypothesize that CD74 expression in BMDM macrophages promotes immunosuppressive macrophage polarization, T cell inactivation and MT.
Methods CD74 expression in LGG and HGG in vivo was evaluated by spatial transcriptomics. CD74 was silenced in primary murine bone-marrow myeloid cells, and the transcriptome was analyzed by RNA sequencing. LGG and HGG CD74 knockdown (KD) BM myeloid cells were co-cultured with primary CD8+ T cells, and T cells activation was assessed by real-time PCR. Additionally, myeloid cells infiltration of the TME after MIF-CD74 inhibition in vivo was measured by flow cytometry.
Results Spatial transcriptomic analysis of the TME demonstrated significant upregulation of MHC class II protein in the LGG TME compared to HGG. Silencing CD74 in primary BM cells resulted in the downregulation of genes associated with migration, proliferation, and immunosuppressive pathways. Co-culture of CD74-silenced LGG BM myeloid cells with primary murine CD8+T cells induced significant upregulation of genes associated with cytotoxic T cells activation. In vivo MIF-CD74 inhibition in LGG mice significantly reduced tumor infiltrating macrophages.
Conclusions These preclinical studies highlight the potential of targeting CD74 to reduce myeloid cells infiltration and enhance CD8+ T cells activation in LGG and improve immunotherapeutic outcomes (figure 1).
References
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Rajendran S, Hu Y, Canella A, Peterson C, Gross A, Cam M, et al. Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma. Cell Rep 2023;42(3):112197.
Xu S, Li X, Tang L, Liu Z, Yang K, Cheng Q. CD74 correlated with malignancies and immune microenvironment in gliomas. Front Mol Biosci 2021;8:706949.
Summary of the project and driving hypothesis
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