Bone morphogenetic protein 7 promotes resistance to immunotherapy

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.

Identification of an Immune Gene-Associated Prognostic Signature and Its Association With a Poor Prognosis in Gastric Cancer Patients

“…Of these, 15 genes ( IGHJ3 , IGLV6-57 , TNFRSF17 , IGLV2-18 , IGHD3-22 , IGHV3-64 , IL2RG , IGHJ1 , IGLV4-60 , IGLV5-48 , IGLC7 , IGHA2 , IL33 , GKN1 , CCL25 ) were upregulated and only 1 gene ( BMP7 ) were downregulated in the Immunity_H group. BMP7 , bone morphogenetic protein 7, can regulate immune cell responses and are immunosuppressive in cancer, which can act as a potential immunotherapeutic target ( 29 ). The log2 fold change values in the DEGs, DEIGs, PIGs, and their FDR values in both Immunity_H and Immunity_L groups were shown in Figure 3D .…”

“…CCL25 (chemotactic cytokines 25) can promote the proliferation by activating the AKT signaling and intratumoral delivery of CCL25 may enhance immunotherapy ( 37 ). BMP7 , a member of the TGFB superfamily, inhibits the MAPK14 signaling pathway and induces resistance to anti-PD1 therapy ( 29 ). Gastrokine 1 ( GKN1 ) has been found to suppress GC cell growth by activating the p16/Rb pathway ( 38 ).…”

The Current Landscape of Immune Checkpoint Blockade in Metastatic Lung Squamous Cell Carcinoma

“…et al found that BMP7 impairs proinflammatory responses in the tumor microenvironment by inhibiting mitogen-activated protein kinase 14 (MAPK14) expression in macrophages and CD4 + T cells. Knockdown of BMP7 in combination with anti-PD1 activates CD4 + and CD8 + T cells in tumors, decreases M2 macrophages, and resensitizes resistant tumors to immunotherapies [ 48 ]. Emerging evidence demonstrates that targeting epigenetic elements that promote tumor progression and inhibit immune cell activity can enhance antitumor immunity by reshaping the TME.…”

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

“…identified two immune subtypes of triple-negative breast cancer, including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES), and the MES-to-NES conversion can mediate acquired ICBs resistance ( 100 ). Furthermore, tumor-derived bone morphogenetic protein 7 (BMP7), a member of the TGF-β superfamily, promotes resistance to immunotherapy ( 101 ). Adenosine is considered an important immunosuppressive cytokine ( 102 ).…”