Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 checkpoint inhibitor therapy by modulating the tumor microenvironment

The nonselective beta blocker, propranolol, which for decades has been used for treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we have investigated the anti-angiogenic properties of propranolol in the context of stimulating an anti-tumor immune response. We show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma tumors and improves the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol-treatment leads to an upregulation of PD-L1 on tumor-associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the efficacy of anti-CTLA4 therapy is significantly enhanced by the co-administration of propranolol. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially also in other cancers. Gene expression analysis of tumor-associated macrophages isolated from MCA205 tumors from control and propranolol treated mice.

非选择性β受体阻滞剂普萘洛尔（propranolol）数十年来一直应用于心血管疾病的临床治疗，近期却被成功用于转移性血管肉瘤（metastatic angiosarcoma）的治疗。上述研究成果推动欧洲药品管理局（European Medicines Agency）为其授予了软组织肉瘤治疗领域的孤儿药资格认定。普萘洛尔的抗肿瘤效应被认为与抑制肿瘤细胞增殖及血管生成密切相关。本研究针对普萘洛尔在激活抗肿瘤免疫应答背景下的抗血管生成活性展开了系统探究。实验结果显示，口服普萘洛尔可延缓MCA205纤维肉瘤（MCA205 fibrosarcoma）的肿瘤进展，并提升荷瘤小鼠的存活率。其作用机制为抑制肿瘤血管生成，并重塑抗肿瘤免疫微环境：可增加T细胞浸润，同时减少髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）的浸润。通过构建T细胞缺陷小鼠模型，本研究证实普萘洛尔的完整抗肿瘤效应依赖于T细胞的存在。对经荧光激活细胞分选（fluorescence-activated cell sorting, FACS）分离的细胞开展流式细胞术分析与RNA测序（RNA sequencing）结果表明，普萘洛尔处理可上调肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）表面的PD-L1表达，并改变其趋化因子表达谱。最后，本研究发现，联合使用普萘洛尔可显著增强抗CTLA4（anti-CTLA4）疗法的疗效。本研究结果证实，普萘洛尔是一种免疫调节剂，可提升软组织肉瘤患者的免疫检查点抑制剂治疗效果，且该效应可能同样适用于其他癌种。本研究同时对来自对照组与普萘洛尔处理组小鼠的MCA205纤维肉瘤组织中分离得到的肿瘤相关巨噬细胞进行了基因表达分析。