Targeting MS4A4A: A novel pathway to improve immunotherapy responses in glioblastoma

• Published in: CNS neuroscience & therapeutics 2024-07, Vol.30 (7), p.e14791-n/a
• Main Authors: Shao, Guangcai, Cui, Xiangguo, Wang, Yiliang, Luo, Shuyan, Li, Chuanyu, Jiang, Yu, Cai, Dasheng, Li, Nu, Li, Xiang
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Brain cancer; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brain tumors; CD8 antigen; Cell Line, Tumor; Cells; Combination therapy; Cytokines; Datasets; Ferroptosis; ferroptosis pathway; Flow cytometry; Gene expression; Glioblastoma; Glioblastoma - immunology; Glioblastoma - pathology; Glioblastoma - therapy; Glioma; Humans; immune checkpoint blockade; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune system; Immunotherapy; Immunotherapy - methods; Infiltration; Lymphocytes T; macrophage polarization; Macrophages; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Mice; Mice, Inbred C57BL; Microenvironments; MS4A4A; PD-1 protein; Phenotypes; Polarization; Software; Spatial distribution; Transcriptomics; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor Microenvironment - physiology; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism
• ISSN: 1755-5930; 1755-5949; 1755-5949
• DOI: 10.1111/cns.14791

Introduction Glioblastoma (GBM) remains a challenging brain tumor to treat, with limited response to PD‐1 immunotherapy due to tumor‐associated macrophages (TAMs), specifically the M2 phenotype. This study explores the potential of MS4A4A (membrane spanning four domains, subfamily A, member 4A) inhibition in driving M2 macrophage polarization toward the M1 phenotype via the ferroptosis pathway to enhance the effectiveness of immunotherapy in GBM. Methods Single‐cell RNA sequencing and spatial transcriptomic analyses were employed to characterize M2 macrophages and MS4A4A expression in GBM. In vitro studies utilizing TAM cultures, flow cytometry, and western blot validations were conducted to assess the impact of MS4A4A on the tumor immune microenvironment and M2 macrophage polarization. In vivo models, including subcutaneous and orthotopic transplantation in mice, were utilized to evaluate the effects of MS4A4A knockout and combined immune checkpoint blockade (ICB) therapy on tumor growth and response to PD‐1 immunotherapy. Results Distinct subsets of GBM‐associated macrophages were identified, with spatial distribution in tumor tissue elucidated. In vivo experiments demonstrated that inhibiting MS4A4A and combining ICB therapy effectively inhibited tumor growth, reshaped the tumor immune microenvironment by reducing M2 TAM infiltration and enhancing CD8+ T‐cell infiltration, ultimately leading to complete tumor eradication. Conclusion MS4A4A inhibition shows promise in converting M2 macrophages to M1 phenotype via ferroptosis, decreasing M2‐TAM infiltration, and enhancing GBM response to PD‐1 immunotherapy. These findings offer a novel approach to developing more effective immunotherapeutic strategies for GBM. This study employs single‐cell transcriptomic analysis to identify subgroups of glioblastoma‐associated macrophages. Spatial transcriptomic analysis reveals the spatial distribution of macrophages within glioblastoma tissue. In vitro experiments demonstrate that inhibition of MS4A4A reduces the immunosuppressive function of M2‐type macrophages. In vivo experiments confirm that inhibition of MS4A4A enhances the response of glioblastoma to PD‐1 immunotherapy. This study provides new theoretical bases and molecular therapeutic targets for the diagnosis and treatment of glioblastoma.