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.
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http://dx.doi.org/10.1111/cns.14791 | DOI Listing |
Front Immunol
December 2024
The Oncology Department of the First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
Background: Uterine clear cell carcinoma (UCCC) is a rare and aggressive subtype of endometrial cancer, often presenting at an advanced stage with poor prognosis. Treatment options for advanced or recurrent UCCC are currently limited, especially after platinum-based chemotherapy has failed.
Case Presentation: We present the case of a 49-year-old female diagnosed with stage IV uterine clear cell carcinoma.
Front Immunol
December 2024
Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Afliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
Background: Inflammation and immune evasion are associated with tumorigenesis and progression. The Systemic Inflammation Response Index (SIRI) has been proposed as a pre-treatment peripheral blood biomarker. This study aims to compare the relationship between SIRI, various serum biomarkers, and the prognosis of NSCLC patients before and after treatment.
View Article and Find Full Text PDFNat Med
January 2025
Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; and Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia.
Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy.
View Article and Find Full Text PDFJ Clin Invest
January 2025
Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Tumor-initiating cells (TICs) play a key role in cancer progression and immune escape. However, how TICs evade immune elimination remains poorly characterized. Combining single-cell RNA sequencing (scRNA-seq), dual-recombinase-based lineage tracing, and other approaches, we identified a WNT-activated subpopulation of malignant cells that act as TICs in vivo.
View Article and Find Full Text PDFJ Immunother Cancer
January 2025
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
Background: Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.
Methods: Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.
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