Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs

Abstract

Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial–mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro . Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.

Tumor microenvironment complexity and therapeutic implications at a glance

“…Similar to their role in normal wound healing process, in the context of cancer, CAFs interaction with tumor cells occurs at several interfaces. CAFs produce ECM proteins, which prompts immunosuppression of tumor cells by recruiting immunosuppressive cells [64,65] such as monocytes and inducing immunosuppressive PD-1+ TAMs, as recently shown in breast cancer cells in vitro [66]. In addition, CAFs promote angiogenesis by producing fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor A (VEGFA) in different cancers [67] as well as galectin-1 expression in gastric cancer [68].…”

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

“…51 Gok et al reported that compared to NFs, CAFs F I G U R E 2 Markers of CAFs could not only recruit monocytes via monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor-1 (SDF-1), but also differentiated monocytes into M2 macrophages with higher expression of IL-10, therefore exerting immunosuppressive roles in breast cancer. 52 In prostate cancer, CAFs are beneficial factors for monocyte recruitment to cancer cells, mainly by transferring stromal derived growth factor-1 and promoting the transformation of macrophages into the M2 phenotype. 53 This complex interaction between tumour cells, CAFs and M2 macrophages enhances the motility of tumour cells, thereby promoting escape from primary tumours, metastatic diffusion and the angiogenesis of endothelial cells.…”

Taking a Full Snapshot of Cancer Biology: Deciphering the Tumor Microenvironment for Effective Cancer Therapy in the Oncology Clinic

“…turn enemies into allies. Mirroring real-life global diplomacy, the re-educating of cancer cells, CAFs, CAMs, and CANs have been proposed as a way to treat cancer (Gok Yavuz et al, 2019;Shen et al, 2016). Controlling the composition of the ECM is another possible strategy (Senthebane et al, 2018).…”