The Mincle/Syk/NF-κB Signalling Circuit is Essential for Maintaining the Protumoral Activities of Tumor-associated Macrophages
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AbstractTumor-associated macrophages (TAM) have important roles in cancer promotion, but the signalling behind the formation of protumoral TAM remains understudied. Here, by single-cell RNA sequencing, we revealed that the pattern recognition receptor Mincle was highly expressed in TAM of patients and significantly associated with the mortality in non-small cell lung cancer patients. Cancer cells markedly induced Mincle expression in bone marrow-derived macrophage (BMDM), thus promoting cancer progression in invasive lung carcinoma LLC and melanoma B16F10 in vivo and in vitro. Mincle was predominately expressed in the M2-like TAM in NSCLC and LLC-tumors and silencing of Mincle unexpectedly promoted M1-like phenotypes in vitro. Mechanistically, we discovered a novel Mincle/Syk/NF-κB signalling pathway in TAM needed for executing their TLR4-independent protumoral activities. Adoptive transfer of Mincle-silenced BMDM significantly suppressed TAM-driven cancer progression in the LLC-bearing NOD/SCID mice. By modifying our well-established ultrasound microbubble-mediated gene transfer protocol, we demonstrated that tumor-specific silencing of Mincle effectively blocked Mincle/Syk/NF-κB signalling, therefore inhibiting the TAM-driven cancer progression in the syngernic mouse cancer models. Thus, our findings highlighted the function of Mincle as a novel immunotherapeutic target for cancer via targeting the Mincle/Syk/NF-κB circuit in TAM.
All Author(s) ListLi C, Xue VW, Wang QM, Lian GY, Huang XR, Lee TL, To KF, Tang PM, Lan HY
Journal nameCancer Immunology Research
Year2020
Month8
Volume Number8
Issue Number8
Pages1004 - 1017
ISSN2326-6066
eISSN2326-6074
LanguagesEnglish-United Kingdom

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