Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Commun. 2020 Sep 24;11(1):4840. doi: 10.1038/s41467-020-18617-z.
Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4 T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.
免疫疗法通过利用免疫系统来靶向癌细胞，从而彻底改变了癌症治疗。然而，大多数患者对免疫疗法具有抗性，而这种抗性的机制仍知之甚少。在这里，我们报告称，TGFB 超家族成员 BMP7 的过表达代表了临床前模型和免疫治疗期间疾病进展的患者对抗 PD-1 治疗产生抗性的一种机制。肿瘤细胞分泌的 BMP7 作用于肿瘤微环境中的巨噬细胞和 CD4 T 细胞，抑制 MAPK14 的表达并损害促炎反应。敲低 BMP7 或通过 follistatin 中和其与抗 PD-1 联合使用可使耐药肿瘤重新对免疫治疗敏感。因此，我们将 BMP7 信号通路鉴定为癌症中潜在的免疫治疗靶标。
