Modulation of tumor inflammatory signaling and drug sensitivity by CMTM4.

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Tác giả: Stuart A Aaronson, Debasish Boral, Shu-Hsia Chen, Brian A Coakley, Celia Divino, Samuel Eisenstein, Bingliang Fang, Mien-Chie Hung, Kyeongah Kang, Junhua Mai, Sunny Mai, Ping-Ying Pan, William Pan, Arshiya Parveen, Won-Min Song, Yuan Shuo Wang, Yitian Xu, Bin Zhang, Licheng Zhang, Junjun Zheng

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: England : The EMBO journal , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 55941

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.
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