Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Cancer Immunol Res. 2020 Aug;8(8):1004-1017. doi: 10.1158/2326-6066.CIR-19-0782. Epub 2020 Jun 12.
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 and 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 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.
肿瘤相关巨噬细胞（TAM）在癌症进展中具有重要作用，但促进肿瘤形成的 TAM 形成信号仍未得到充分研究。在这里，通过单细胞 RNA 测序，我们揭示了模式识别受体 Mincle 在 TAM 中高度表达，并与非小细胞肺癌患者的死亡率显著相关。癌细胞在骨髓来源的巨噬细胞（BMDM）中显著诱导 Mincle 表达，从而促进侵袭性肺腺癌 LLC 和黑色素瘤 B16F10 的癌症进展，并且 Mincle 在非小细胞肺癌和 LLC 肿瘤中的 M2 样 TAM 中表达为主，沉默 Mincle 出人意料地促进了 M1 样表型。在机制上，我们在 TAM 中发现了一种新的 Mincle/Syk/NF-κB 信号通路，该通路需要执行其 TLR4 非依赖性促肿瘤活性。Mincle 沉默的 BMDM 的过继转移显著抑制了 LLC 荷瘤 NOD/SCID 小鼠中的 TAM 驱动的癌症进展。通过修改我们成熟的超声微泡介导的基因转移方案，我们证明了肿瘤特异性沉默 Mincle 可有效阻断 Mincle/Syk/NF-κB 信号通路，从而抑制同源小鼠癌症模型中的 TAM 驱动的癌症进展。因此，我们的研究结果强调了 Mincle 作为一种新型免疫治疗靶点的功能，通过阻断 TAM 中的 Mincle/Syk/NF-κB 回路来抑制癌症进展。
