Nature Communications ( IF 16.6 ) Pub Date : 2020-09-24 , DOI: 10.1038/s41467-020-18617-z Maria Angelica Cortez 1 , Fatemeh Masrorpour 1 , Cristina Ivan 2 , Jie Zhang 3 , Ahmed I Younes 1 , Yue Lu 4 , Marcos R Estecio 4 , Hampartsoum B Barsoumian 1 , Hari Menon 1 , Mauricio da Silva Caetano 3 , Rishab Ramapriyan 1 , Jonathan E Schoenhals 3 , Xiaohong Wang 3 , Ferdinandos Skoulidis 5 , Mark D Wasley 1 , George Calin 2 , Patrick Hwu 6 , James W Welsh 1
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.
中文翻译:
骨形态发生蛋白 7 促进对免疫疗法的抵抗
免疫疗法通过利用免疫系统靶向癌细胞,彻底改变了癌症治疗。然而,大多数患者对免疫疗法有抵抗力,而这种抵抗力背后的机制仍然知之甚少。在这里,我们报告了 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患者对抗 PD1 治疗产生耐药性的机制。肿瘤细胞分泌的 BMP7 作用于巨噬细胞和 CD4 +肿瘤微环境中的 T 细胞,抑制 MAPK14 表达并削弱促炎反应。结合抗 PD1 抑制 BMP7 或通过卵泡抑素中和其使耐药肿瘤对免疫疗法重新敏感。因此,我们将 BMP7 信号通路确定为癌症中潜在的免疫治疗靶点。