Purpose: To explore the cellular crosstalk of tumor resident mast cells (MCs) in controlling the activity of cancer-associated fibroblasts (CAFs) to overcome TME abnormalities, enhancing the efficacy of immune checkpoint inhibitors (ICIs) 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 repurpose 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 chemo-immunotherapy, 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.

中文翻译：

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稳定肿瘤驻留肥大细胞可恢复 T 细胞浸润并使肉瘤对 PD-L1 抑制敏感

目的：探讨肿瘤驻留肥大细胞 (MC) 在控制癌症相关成纤维细胞 (CAF) 活性以克服 TME 异常方面的细胞串扰，从而增强免疫检查点抑制剂 (ICIs) 在肉瘤中的疗效。实验设计：我们使用共培养系统，然后在使用或不使用 MC 稳定剂和抗组胺酮替芬的小鼠纤维肉瘤和骨肉瘤模型中进行进一步验证。为了评估酮替芬在使肿瘤对治疗敏感方面的贡献，我们进行了阿霉素化疗和抗 PD-L1（B7-H1，克隆 10F.9G2）治疗的联合研究。我们在一项重新调整用途的 II 期临床试验中研究了酮替芬调节人类肉瘤 TME 的能力。结果：超声剪切波弹性成像显示，用酮替芬抑制 MC 活化成功抑制了 CAF 增殖和细胞外基质僵硬，同时纤维肉瘤和骨肉瘤中血管灌注增加。组织氧合的改善提高了化学免疫疗法的疗效，并得到增强的 T 细胞浸润和肿瘤抗原特异性记忆的获得的支持。重要的是，酮替芬降低肿瘤硬度的作用在肉瘤患者中得到了进一步验证，突显了其转化潜力。结论：我们的研究表明，用临床药物（例如抗组胺药）靶向 MC，是克服肉瘤免疫治疗耐药性的一种有前途的方法。