医学
癌症研究
肉瘤
纤维肉瘤
肿瘤微环境
酮替芬
阿霉素
免疫系统
免疫疗法
病理
药理学
化疗
免疫学
内科学
哮喘
作者
Myrofora Panagi,Fotios Mpekris,Chrysovalantis Voutouri,Andreas G. Hadjigeorgiou,Chloe Symeonidou,Eleni Porfyriou,Christina Michael,Andreas Stylianou,John D. Martin,Horacio Cabral,Anastasia Constantinidou,Triantafyllos Stylianopoulos
标识
DOI:10.1158/1078-0432.ccr-24-0246
摘要
Abstract Purpose: To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma. Experimental Design: We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti–PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial. Results: Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen–specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential. Conclusions: Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.
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