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

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, α-smooth muscle actin (α-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, TGFβ is a TAM-secreted cytokine involved in CAF activation. We also observed that TGFβ 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, TGFβ 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 TGFβ secretion) can perturb this positive feedback loop within the tumor ecologic niche (Fig. 1G). Particularly, our finding that IL6 and GM-CSF induces TGFβ expression in differentiating monocytes can be significant, because TGFβ-mediated programming of the stroma initiates metastasis in colorectal cancer (4). Because of the importance of CAF in protumorigenic signaling, immunologic responses, and drug resistance (5, 6), current studies in our laboratory are focused on further deciphering the broad implications of CAF–TAM interactions.

See the original Letter to the Editor, p. 892