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EMBO J., 13 February 2025 | https://doi.org/10.1038/s44318-024-00330-y
Modulation of tumor inflammatory signaling and drug sensitivity by CMTM4
Yitian Xu 1,2,11, Kyeongah Kang 1,2,11, Brian A Coakley 3,4, Samuel Eisenstein 4, Arshiya Parveen 1,2, Sunny Mai 1,2, Yuan Shuo Wang 1,3,4, Junjun Zheng 1,2, Debasish Boral 1, Junhua Mai 5, William Pan 3, Licheng Zhang 1,2, Stuart A Aaronson 3, Bingliang Fang 6, Celia Divino 4, Bin Zhang 7, Won-Min Song 7, Mien-Chie Hung 8, Ping-Ying Pan 1 & Shu-Hsia Chen 1,2,3,4,9,10,*
1Immunotherapy Research Center, Houston Methodist Research Institute, Houston, TX 77030, USA.
2Neal Cancer Center of Excellence, Houston Methodist Research Institute,Houston, TX 77030, USA.
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4Department of Surgery, Icahn School ofMedicine at Mount Sinai, New York, NY 10029, USA.
5Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
6Department of Thoracicand Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX 77030, USA.
7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai,New York, NY 10029, USA.
8Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University,Taichung, Taiwan.
9Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medical Science and Graduate School of Medical Sciences, New York, NY 10065,USA.
10Graduate and professional school at Texas A&M University, 400 Bizzell St., College Station, TX 77840, USA.
11These authors contributed equally: Yitian Xu, Kyeongah Kang.
2Neal Cancer Center of Excellence, Houston Methodist Research Institute,Houston, TX 77030, USA.
3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4Department of Surgery, Icahn School ofMedicine at Mount Sinai, New York, NY 10029, USA.
5Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
6Department of Thoracicand Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX 77030, USA.
7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai,New York, NY 10029, USA.
8Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University,Taichung, Taiwan.
9Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medical Science and Graduate School of Medical Sciences, New York, NY 10065,USA.
10Graduate and professional school at Texas A&M University, 400 Bizzell St., College Station, TX 77840, USA.
11These authors contributed equally: Yitian Xu, Kyeongah Kang.
*Corresponding author: correspondence to Shu-Hsia Chen
Abstract
Although inflammation has been widely associated with cancer development, how it affects the outcomes of immunotherapy and chemotherapy remains incompletely understood. Here, we show that CKLF-like MARVEL transmembrane domain-containing member 4 (CMTM4) is highly expressed in multiple human and murine cancer types including Lewis lung carcinoma, triple-negative mammary cancer and melanoma. In lung carcinoma, loss of CMTM4 significantly reduces tumor growth and impairs NF-κB, mTOR, and PI3K/Akt pathway activation. Furthermore, we demonstrate that CMTM4 can regulate epidermal growth factor (EGF) signaling post-translationally by promoting EGFR recycling and preventing its Rab-dependent degradation. Consequently, CMTM4 knockout sensitizes human lung tumor cells to EGFR inhibitors. In addition, CMTM4 knockout tumors stimulated with EGF show a decreased ability to produce inflammatory cytokines including granulocyte colony-stimulating factor (G-CSF), leading to decreased recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and therefore establishing a less suppressive tumor immune environment in both lung and mammary cancers. We also present evidence indicating that CMTM4-targeting siRNA-loaded liposomes reduce lung tumor growth in vivo and prolong animal survival. Knockout of CMTM4 enhances immune checkpoint blockade or chemotherapy to further reduce lung tumor growth. These data suggest that CMTM4 represents a novel target for the inhibition of tumor inflammation, and improvement of the immune response and tumor drug sensitivity.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-17)
- 국외 연구진
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