The Mincle/Syk/NF-κB Signaling Circuit Is Essential for Maintaining the Protumoral Activities of Tumor-Associated Macrophages.
Chunjie LiVivian Weiwen XueQing-Ming WangGuang-Yu LianXiao-Ru HuangTin-Lap LeeKa-Fai ToPatrick Ming-Kuen TangHui Yao LanPublished in: Cancer immunology research (2020)
Tumor-associated macrophages (TAM) have important roles in cancer progression, but the signaling 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 and significantly associated with mortality in patients with non-small cell lung cancer. Cancer cells markedly induced Mincle expression in bone marrow-derived macrophages (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 non-small cell lung carcinoma and LLC tumors, and silencing of Mincle unexpectedly promoted M1-like phenotypes in vitro Mechanistically, we discovered a novel Mincle/Syk/NF-κB signaling 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 signaling, therefore inhibiting the TAM-driven cancer progression in the syngeneic mouse cancer models. Thus, our findings highlight the function of Mincle as a novel immunotherapeutic target for cancer via blocking the Mincle/Syk/NF-κB circuit in TAM.
Keyphrases
- signaling pathway
- papillary thyroid
- single cell
- squamous cell
- pi k akt
- tyrosine kinase
- oxidative stress
- lps induced
- randomized controlled trial
- squamous cell carcinoma
- inflammatory response
- poor prognosis
- epithelial mesenchymal transition
- lymph node metastasis
- nuclear factor
- toll like receptor
- type diabetes
- cell therapy
- childhood cancer
- risk factors
- long non coding rna
- adipose tissue
- diabetic rats
- skeletal muscle
- stress induced