Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; NextGen Precision Health Institute, University of Missouri-Columbia, Columbia, MO, 65212, USA.
Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
Cancer Lett. 2023 Dec 1;578:216457. doi: 10.1016/j.canlet.2023.216457. Epub 2023 Oct 19.
Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC) tumorigenesis from initiation to angiogenesis, growth, and systemic dissemination, as well as immunosuppression and resistance to chemotherapy and immunotherapy; however, the critical intrinsic factors responsible for TAMs reprograming and function remain to be identified. By performing single-cell RNA sequencing, transforming growth factor-beta-induced protein (TGFBI) was identified as TAM-producing factor in murine PaC tumors. TAMs express TGFBI in human PaC and TGFBI expression is positively related with human PaC growth. By inducing TGFBI loss-of-function in macrophage (MΦs) in vitro with siRNA and in vivo with Cre-Lox strategy in our developed TGFBI-floxed mice, we demonstrated disruption of TGFBI not only inhibited MΦ polarization to M2 phenotype and MΦ-mediated stimulation on PaC growth, but also significantly improved anti-tumor immunity, sensitizing PaC to chemotherapy in association with regulation of fibronectin 1, Cxcl10, and Ccl5. Our studies suggest that targeting TGFBI in MΦ can develop an effective therapeutic intervention for highly lethal PaC.
肿瘤相关巨噬细胞（TAMs）作为肿瘤微环境（TME）的主要和必需组成部分，在协调胰腺癌（PaC）从起始到血管生成、生长和全身扩散以及免疫抑制和对化疗和免疫治疗的耐药性的肿瘤发生中起着关键作用；然而，导致 TAMs 重新编程和功能的关键内在因素仍有待确定。通过单细胞 RNA 测序，转化生长因子-β诱导蛋白（TGFBI）被鉴定为小鼠 PaC 肿瘤中产生 TAMs 的因子。TAMs 在人类 PaC 中表达 TGFBI，TGFBI 的表达与人类 PaC 的生长呈正相关。通过在体外用 siRNA 和在我们开发的 TGFBI 敲除小鼠中用 Cre-Lox 策略在巨噬细胞（MΦ）中诱导 TGFBI 功能丧失，我们证明了 TGFBI 的缺失不仅抑制了 MΦ向 M2 表型的极化和 MΦ介导的对 PaC 生长的刺激，而且还显著改善了抗肿瘤免疫，使 PaC 对化疗敏感，并与纤维连接蛋白 1、Cxcl10 和 Ccl5 的调节有关。我们的研究表明，靶向 MΦ中的 TGFBI 可以为高度致命的 PaC 开发一种有效的治疗干预措施。
