Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology
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Bone Morphogenetic Protein 7 / genetics*
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Bone Morphogenetic Protein 7 / metabolism*
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CD4-Positive T-Lymphocytes
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects*
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Female
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Follistatin / metabolism
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Humans
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Immunotherapy / methods*
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Mice
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Mitogen-Activated Protein Kinase 14 / genetics
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Mitogen-Activated Protein Kinase 14 / metabolism
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Neoplasms / metabolism*
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Programmed Cell Death 1 Receptor / drug effects
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RAW 264.7 Cells
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Smad1 Protein / metabolism
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Transcriptome
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Tumor Microenvironment / drug effects
Substances
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Antibodies, Monoclonal, Humanized
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BMP7 protein, human
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Bone Morphogenetic Protein 7
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Follistatin
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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SMAD1 protein, human
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Smad1 Protein
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atezolizumab
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Mitogen-Activated Protein Kinase 14