1. EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer
- Author
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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, Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, Cold Spring Harbor Laboratory (CSHL), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), The University of Texas M.D. Anderson Cancer Center [Houston], Nanjing University of Science and Technology (NJUST), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Sun Yat-Sen University [Guangzhou] (SYSU), and Department of Breast Medical Oncology [Houston]
- Subjects
Multidisciplinary ,[SDV]Life Sciences [q-bio] ,Human medicine - 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.
- Published
- 2022