Bone morphogenetic protein 7 promotes resistance to immunotherapy

Maria Angelica Cortez; Fatemeh Masrorpour; Cristina Ivan; Jie Zhang; Ahmed Younes; Yue Lu; Marcos R. Estecio; Hampartsoum B. Barsoumian; Hari Menon; Mauricio da Silva Caetano; Rishab Ramapriyan; Jonathan E. Schoenhals; Xiaohong Wang; Ferdinandos Skoulidis; Mark D. Wasley; George Calin; Patrick Hwu; James W. Welsh

doi:10.1038/s41467-020-18617-z

Bone morphogenetic protein 7 promotes resistance to immunotherapy

Maria Angelica Cortez, Fatemeh Masrorpour, Cristina Ivan, Jie Zhang, Ahmed Younes, Yue Lu, Marcos R. Estecio, Hampartsoum B. Barsoumian, Hari Menon, Mauricio da Silva Caetano, Rishab Ramapriyan, Jonathan E. Schoenhals, Xiaohong Wang, Ferdinandos Skoulidis, Mark D. Wasley, George Calin, Patrick Hwu, James W. Welsh

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English (US)
Article number	4840
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18617-z
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Flow Cytometry and Cellular Imaging Facility
Functional Genomics Core
Epigenomics Profiling Core Facility
Bioinformatics Shared Resource
Functional Proteomics Reverse Phase Protein Array Core

Access to Document

10.1038/s41467-020-18617-z

Cite this

Cortez, M. A., Masrorpour, F., Ivan, C., Zhang, J., Younes, A., Lu, Y., Estecio, M. R., Barsoumian, H. B., Menon, H., Caetano, M. D. S., Ramapriyan, R., Schoenhals, J. E., Wang, X., Skoulidis, F., Wasley, M. D., Calin, G., Hwu, P., & Welsh, J. W. (2020). Bone morphogenetic protein 7 promotes resistance to immunotherapy. Nature communications, 11(1), Article 4840. https://doi.org/10.1038/s41467-020-18617-z

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 & Welsh, JW 2020, 'Bone morphogenetic protein 7 promotes resistance to immunotherapy', Nature communications, vol. 11, no. 1, 4840. https://doi.org/10.1038/s41467-020-18617-z

@article{06933be614b846b2b7b30ef2ad1fae6e,

title = "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.",

author = "Cortez, {Maria Angelica} and Fatemeh Masrorpour and Cristina Ivan and Jie Zhang and Ahmed Younes and Yue Lu and Estecio, {Marcos R.} and Barsoumian, {Hampartsoum B.} and Hari Menon and Caetano, {Mauricio da Silva} and Rishab Ramapriyan and Schoenhals, {Jonathan E.} and Xiaohong Wang and Ferdinandos Skoulidis and Wasley, {Mark D.} and George Calin and Patrick Hwu and Welsh, {James W.}",

note = "Funding Information: We thank Christine F. Wogan, MS, ELS, and Joe D. Dunn of MD Anderson{\textquoteright}s Division of Radiation Oncology, for editorial contributions. WE thank David Aten, Senior Medical Illustrator of MD Anderson Strategic—Creative Communication for illustration contributions. This work was supported by American Lung Association Award #RG-514395; the Mabuchi Research Fund; the family of M. Adnan Hamed; the Susan and Peter Goodwin Foundation; the Orr Family Foundation (to MD Anderson Cancer Center{\textquoteright}s Thoracic Radiation Oncology program); and the Wiegand Foundation and the Cancer Center Support (Core) grant CA016672 to The University of Texas MD Anderson Cancer Center from the National Cancer Center, National Institutes of Health. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-18617-z",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Bone morphogenetic protein 7 promotes resistance to immunotherapy

AU - Cortez, Maria Angelica

AU - Masrorpour, Fatemeh

AU - Ivan, Cristina

AU - Zhang, Jie

AU - Younes, Ahmed

AU - Lu, Yue

AU - Estecio, Marcos R.

AU - Barsoumian, Hampartsoum B.

AU - Menon, Hari

AU - Caetano, Mauricio da Silva

AU - Ramapriyan, Rishab

AU - Schoenhals, Jonathan E.

AU - Wang, Xiaohong

AU - Skoulidis, Ferdinandos

AU - Wasley, Mark D.

AU - Calin, George

AU - Hwu, Patrick

AU - Welsh, James W.

N1 - Funding Information: We thank Christine F. Wogan, MS, ELS, and Joe D. Dunn of MD Anderson’s Division of Radiation Oncology, for editorial contributions. WE thank David Aten, Senior Medical Illustrator of MD Anderson Strategic—Creative Communication for illustration contributions. This work was supported by American Lung Association Award #RG-514395; the Mabuchi Research Fund; the family of M. Adnan Hamed; the Susan and Peter Goodwin Foundation; the Orr Family Foundation (to MD Anderson Cancer Center’s Thoracic Radiation Oncology program); and the Wiegand Foundation and the Cancer Center Support (Core) grant CA016672 to The University of Texas MD Anderson Cancer Center from the National Cancer Center, National Institutes of Health. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85091448732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85091448732&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-18617-z

DO - 10.1038/s41467-020-18617-z

M3 - Article

C2 - 32973129

AN - SCOPUS:85091448732

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4840

ER -

Bone morphogenetic protein 7 promotes resistance to immunotherapy

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this