Authors:

Natalie E. Reitz

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Not specified

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About Paper:

' Department of Cancer Sciences, Cleveland Clinic, Cleveland, OH , 44196 ° Heart, Blood, and Kidney Research, Cleveland Clinic, Cleveland, OH 44196 4 Cleveland Clinic Research, Cleveland Clinic, Cleveland ,OH 44196 ® Case Comprehensive Cancer Center, Cleveland, OH 44196 'Cleveland Clinic Lerner College of Medicine of Case Western University Cleveland, OH 44196 9 Case Western Reserve University School of Medicine, Cleveland, OH 44196 Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20800 'NIH Oxford-Cambridge Scholars Program, National Institutes of Health, Bethesda, MD, 20800 / Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44196 * Departments of Pathology and Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 ' Microbial Sciences in Health, Cleveland Clinic, Cleveland OH 44196 ™ Department of Medicine, Hematology, and Oncology Division, Case Western Reserve University School of Medicine, Cleveland OH " Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland OH 44196 email: nataliereitz2027@u.northwestern.edu *PI: lathiaj@ccf.org Glioblastoma (GBM) is the most common primary malignant brain tumor, with outcomes shaped by biological sex differences that influence disease progression, immune function, and interactions within the tumor microenvironment (TME). Although platelets are increasingly recognized as active participants in tumor biology, their contribution to sex-specific immune regulation in GBM has not yet been defined. Here, we identify platelet PAR4 signaling as a central mechanism linking sex hormones to antitumor immunity. To investigate the role of platelets in the immunosuppressive TME, we integrated analyses of human platelet function, multiple murine GBM models, genetic and pharmacologic perturbation of PAR4, hormone manipulation, and immune profiling of tumor-infiltrating cells. We found that GBM patients display elevated platelet activation driven by protease-activated receptor 4 (PAR4). In mouse models of GBM, both pharmacologic inhibition of PAR4 and genetic deletion of PAR4 markedly extend survival in females but not males. This benefit is estrogen dependent, as we have shown using in vivo and in vitro models. Mechanistically, PAR4 inhibition enhances CD8* T-cell infiltration into the TME,establishing a platelet-driven, sex specific immune response. We further show that estrogen receptor B (ER§) physically interacts with PAR4 to amplify calcium signaling in platelets, revealing a previously unrecognized hormone-receptor crosstalk that shapes platelet behavior in tumors. PAR4-activated platelets suppress CD8+ T-cell function within the TME, and depletion of CD8+ T cells eliminates both the heightened platelet reactivity induced by GBM and the survival advantage conferred by PAR4 inhibition. Together, these findings position platelet PAR4 signaling as a key regulator of GBM progression and demonstrate that sex-dependent immune mechanisms critically determine therapeutic efficacy. This work highlights a mechanistic link between estrogen signaling, platelet activation, and antitumor immunity, offering new therapeutic targets for sex-dependent treatment of GBM.

Source:

Northwestern University

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Co-authors:

Natalie E. Reitz