Cortez MA, Masrorpour F, Ivan C, Zhang J, Younes A, Lu Y, Estecio MR, Barsoumian HB, Menon H, Caetano MDS, Ramapriyan R, Schoenhals JE, Wang X, Skoulidis F, Wasley MD, Calin G, Hwu P and Welsh JW.
Nat Commun 11, 4840 (2020).
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.