CAF-Derived IL6 and GM-CSF Cooperate to Induce M2-like TAMs–Response

Abstract

We read with great interest the letter by Iorio and colleagues entitled "Cancer-stimulated CAFs enhance monocyte differentiation and pro-tumoral TAM activation" in this issue of Clinical Cancer Research, which provides valuable context and additional discussion of our recent article in this journal. In their letter, the authors reevaluated their recent work on the role of BAG3, a regulator of chaperone-assisted selective autophagy, which inhibits tumorigenesis and metastasis in pancreatic ductal adenocarcinoma (1, 2). They report reductions in cancer-associated fibroblast (CAF) activation and lowered collagen deposition in both syngeneic and patient-derived xenograft models of pancreatic cancer treated with BAG3 antibodies.In light of these new findings, we have also assessed CAF activation in our orthotopic syngeneic colon carcinoma model. We previously demonstrated that dual blockade with anti-IL6 and anti-granulocyte macrophage colony-stimulating factor (GM-CSF) decreased tumor growth, metastasis, and the presence of M2-like tumor-associated macrophages (TAM; ref.3). Using similar analytical techniques as Iorio and colleagues we can report that CAF activation is also decreased by anti-IL6 and anti-GM-CSF treatment. Expression of the CAF activation marker, a-smooth muscle actin (a-SMA), was reduced in the colon tumor tissue after dual blockade ( Fig. 1A and B). In addition, collagen deposition in the tumors was decreased (Fig. 1C and D). These results from our colon carcinoma model are in accordance with the downregulation of CAF activation reported by Iorio and colleagues in their model of pancreatic ductal adenocarcinoma. As described by Iorio and colleagues, TGFb is a TAM-secreted cytokine involved in CAF activation. We also observed that TGFb can activate normal fibroblasts into the CAF phenotype, whereas IL10, a major component of the M2-like TAMs secretome, had no significant effect (Fig. 1E). In addition, TGFb expression can be induced in bone marrow-derived monocytes by treatment with IL6 or GM-CSF (Fig. 1F). These additional data compliment the findings of Iorio and colleagues and suggest that blockade strategies targeting TAM activation by CAF (such as anti-BAG3, dual anti-IL6/anti-GM-CSF) or the reciprocal CAF activation by TAMs (via TGFb secretion) can perturb this positive feedback loop within the tumor ecologic niche (Fig. 1G). Particularly, our finding that IL6 and GM-CSF induces TGFb expression in differentiating monocytes can be significant, because TGFb-mediated programming of

MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping

“…In our model, macroH2A-dependent regulatory mechanisms converged on a small set of inflammatory genes, which underscores a role for macroH2A in limiting inflammatory signalling in vivo. Notably, CAFs hijack these inflammatory genes as a mechanism of tumour immune escape 80 – 83 , and our studies suggest that dKO CAFs promote an immunosuppressive environment that leads to increased melanoma burden (Fig. 7h ).…”

Colony Stimulating Factor-1 and its Receptor in Gastrointestinal Malignant Tumors

“…Recombinant human granulocyte colony-stimulating factor (rhGCSF) has been widely used in the treatment of granulocytopenia induced by chemoradiotherapy. In vitro studies have shown that CSF can also be produced by tumor cells and stromal cells, and it could promote tumor fitness and cell proliferation and metastasis 67 . Patients with high CSF expression have a rapid disease progression and short survival time.…”