M2-Type Macrophages Induce Tregs Generation by Activating the TGF-β/Smad Signalling Pathway to Promote Colorectal Cancer Development

Xueqian Ma,1 Yu Gao,2 Yanlei Chen,1 Jinhao Liu,1 Chunyu Yang,3 Cuifen Bao,4 Yanping Wang,1 Yang Feng,1 Xiaoyu Song,1 Shifeng Qiao1 1The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, People’s Republic of China; 2Computer Teaching and Research Section, Jinzhou Medical University, Jinzhou, 121000, Liaoning, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, People’s Republic of China; 4Basic Medical Experimental Teaching Center, Jinzhou Medical University, Jinzhou, 121000, Liaoning, People’s Republic of ChinaCorrespondence: Shifeng QiaoThe Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2 Section 5, Renmin Street, Guta District, Jinzhou, Liaoning, 121001, People’s Republic of ChinaTel +86 15904161717Email shifengqiao2020@163.comPurpose: The increase of both M2-type macrophages and Tregs is closely associated with the development of colorectal cancer. However, the mechanism of their interaction is still unclear. In this study, we investigated the correlation of M2-type macrophages with Tregs and the possible mechanisms between them.Methods: Using immunohistochemistry, we analysed Smad3 (a key protein in the TGF-β/Smad signalling pathway) expression in colorectal cells, as well as infiltrating numbers of CD163 (a marker for M2-type macrophages), Foxp3 (a marker for Tregs) in 250 surgically resected colorectal cancer tissues, matched normal and paracancerous tissues. The relation of CD163 and Foxp3 was investigated in CRC with clinicopathological characteristics and preoperative tumour markers.Results: CD163, Foxp3 and Smad3 were upregulated in CRC tissues compared to matched normal and paracancerous tissues. Interestingly, CD163 and Foxp3 were significantly positively correlated in CRC, and both were significantly positively correlated with Smad3. Both CD163 and Foxp3 were upregulated with increasing tumour TNM staging, increasing number of lymph node metastases and increasing vascular invasion. Additionally, CD163 was upregulated with increasing depth of infiltration. The number of M2-type macrophages and the expression levels of preoperative CEA, CA19-9 and CA72-4 were significantly positively correlated. The number of Tregs was significantly positively correlated with the expression levels of preoperative CEA and CA19-9.Conclusion: M2-type macrophages may induce Tregs generation through activation of the TGF-β/Smad signalling pathway, which can promote the development of colorectal cancer.Keywords: M2-type macrophages, Tregs, TGF-β/Smad signalling pathway, CD163, Foxp3, colorectal cancer, CRC