EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

Xiaoping Wang; Takashi Semba; Ganiraju C. Manyam; Jing Wang; Shan Shao; Francois Bertucci; Pascal Finetti; Savitri Krishnamurthy; Lan Thi Hanh Phi; Troy Pearson; Steven J. Van Laere; Jared K. Burks; Evan N. Cohen; James M Reuben; Fei Yang; Hu Min; Nicholas Navin; Van Ngu Trinh; Toshiaki Iwase; Harsh Batra; Yichao Shen; Xiang Zhang; Debu Tripathy; Naoto T. Ueno

doi:10.1126/sciadv.abn7983

EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

Xiaoping Wang, Takashi Semba, Ganiraju C. Manyam, Jing Wang, Shan Shao, Francois Bertucci, Pascal Finetti, Savitri Krishnamurthy, Lan Thi Hanh Phi, Troy Pearson, Steven J. Van Laere, Jared K. Burks, Evan N. Cohen, James M Reuben, Fei Yang, Hu Min, Nicholas Navin, Van Ngu Trinh, Toshiaki Iwase, Harsh BatraYichao Shen, Xiang Zhang, Debu Tripathy, Naoto T. Ueno

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Abstract

Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti-PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.

Original language	English (US)
Article number	abn7983
Journal	Science Advances
Volume	8
Issue number	50
DOIs	https://doi.org/10.1126/sciadv.abn7983
State	Published - Dec 2022

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Wang, X., Semba, T., Manyam, G. C., Wang, J., Shao, S., Bertucci, F., Finetti, P., Krishnamurthy, S., Phi, L. T. H., Pearson, T., Van Laere, S. J., Burks, J. K., Cohen, E. N., Reuben, J. M., Yang, F., Min, H., Navin, N., Trinh, V. N., Iwase, T., ... Ueno, N. T. (2022). EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer. Science Advances, 8(50), Article abn7983. https://doi.org/10.1126/sciadv.abn7983

Wang, X, Semba, T, Manyam, GC, Wang, J, Shao, S, Bertucci, F, Finetti, P, Krishnamurthy, S, Phi, LTH, Pearson, T, Van Laere, SJ, Burks, JK , Cohen, EN, Reuben, JM, Yang, F, Min, H, Navin, N, Trinh, VN, Iwase, T, Batra, H, Shen, Y, Zhang, X, Tripathy, D & Ueno, NT 2022, 'EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer', Science Advances, vol. 8, no. 50, abn7983. https://doi.org/10.1126/sciadv.abn7983

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title = "EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer",

abstract = "Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti-PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.",

author = "Xiaoping Wang and Takashi Semba and Manyam, {Ganiraju C.} and Jing Wang and Shan Shao and Francois Bertucci and Pascal Finetti and Savitri Krishnamurthy and Phi, {Lan Thi Hanh} and Troy Pearson and {Van Laere}, {Steven J.} and Burks, {Jared K.} and Cohen, {Evan N.} and Reuben, {James M} and Fei Yang and Hu Min and Nicholas Navin and Trinh, {Van Ngu} and Toshiaki Iwase and Harsh Batra and Yichao Shen and Xiang Zhang and Debu Tripathy and Ueno, {Naoto T.}",

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year = "2022",

month = dec,

doi = "10.1126/sciadv.abn7983",

language = "English (US)",

volume = "8",

journal = "Science Advances",

issn = "2375-2548",

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T1 - EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

AU - Wang, Xiaoping

AU - Semba, Takashi

AU - Manyam, Ganiraju C.

AU - Wang, Jing

AU - Shao, Shan

AU - Bertucci, Francois

AU - Finetti, Pascal

AU - Krishnamurthy, Savitri

AU - Phi, Lan Thi Hanh

AU - Pearson, Troy

AU - Van Laere, Steven J.

AU - Burks, Jared K.

AU - Cohen, Evan N.

AU - Reuben, James M

AU - Yang, Fei

AU - Min, Hu

AU - Navin, Nicholas

AU - Trinh, Van Ngu

AU - Iwase, Toshiaki

AU - Batra, Harsh

AU - Shen, Yichao

AU - Zhang, Xiang

AU - Tripathy, Debu

AU - Ueno, Naoto T.

PY - 2022/12

Y1 - 2022/12

N2 - Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti-PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.

AB - Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti-PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.

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EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

Abstract

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MD Anderson CCSG core facilities

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