FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

Abstract

Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression are not fully understood. Here, we show that the fibroblast activation protein (FAP) triggers induction of a CAF subset with an inflammatory phenotype directed by STAT3 activation and inflammation-associated expression signature marked by CCL2 upregulation. Enforcing FAP expression in normal fibroblasts was sufficient to endow them with an inflammatory phenotype similar to FAP þ CAFs. We identified FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. In a murine liver tumor model, we found that FAP þ CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC). The CCL2 receptor CCR2 was expressed on circulating MDSCs in tumor-bearing subjects and FAP þ CAF-mediated tumor promotion and MDSC recruitment was abrogated in Ccr2-deficient mice. Clinically, we observed a positive correlation between stromal expression of FAP, p-STAT3, and CCL2 in human intrahepatic cholangiocarcinoma, a highly aggressive liver cancer with dense desmoplastic stroma, where elevated levels of stromal FAP predicted a poor survival outcome. Taken together, our results showed how FAP-STAT3-CCL2 signaling in CAFs was sufficient to program an inflammatory component of the tumor microenvironment, which may have particular significance in desmoplasia-associated cancers. CancerRes; 76(14); 4124-35. Ó2016 AACR.

Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma

“…Preliminary findings from our ongoing studies suggest that disruption of FAP protease inhibits pulmonary metastatic outgrowth and that this inhibition correlates with reduced macrophage infiltration (A. Lo et al, unpublished observations), which may be due to downregulation of CCL2 from FAP-deficient CAFs (12,13). Further studies are required to determine if this mechanism can be extended to PDA metastasis.…”

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

“…There is now ample evidence that CAF produce a large array of chemokines, including the ones specific for granulocytes, such as CXCL1 (Feig et al, 2013; Orimo and Weinberg, 2006). It has recently been reported that CAF also promote migration of monocytic cells to tumors (Yang et al, 2016), but the direct effect of fibroblasts on neutrophil migration has not been previously demonstrated. In our study, PMN-MDSC recruitment by CAF is consistent with the ability of CAF to produce granulocytic chemokines.…”

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…Incipient data are showing the role of the AXL in the paracrine feedback loop between cancer and fibroblastic cells with significant effects on resistance to conventional therapies, and likely, immunotherapy [149], paving the way for the design of new therapeutic strategies combining AXL targeting with ICBs. Growing evidence shows that FAP, selectively expressed on CAF subtypes and associated with ECM remodeling, induces tumor-promoting inflammation [150][151][152]. Furthermore, as mentioned before, FAP targeting has been shown to synergize with ICB-based immunotherapy [120,150,152].…”

“…Growing evidence shows that FAP, selectively expressed on CAF subtypes and associated with ECM remodeling, induces tumor-promoting inflammation [150][151][152]. Furthermore, as mentioned before, FAP targeting has been shown to synergize with ICB-based immunotherapy [120,150,152].…”