Activation of Dectin-1 on Macrophages Promotes Pancreatic Cancer

Pancreatic adenocarcinoma (PDAC) development and progression is significantly influenced by the presence of an inflammatory response mediated by innate immune subsets in the tumor microenvironment (TME), particularly M2-polarized tumor-associated macrophages (TAM) and cells of myeloid-monocytic lineages, but the drivers of the immune-suppressive phenotype of these monocytic subsets have not been definitively identified. The C-type lectin receptor dectin-1 (encoded by CLEC7A), which is expressed on macrophages and cells of the myeloid-monocytic lineages, is critical for the recognition of β-glucans to activate SYK and drive the antifungal immune response, but has no known role in antitumor immunity. To determine whether dectin-1 promotes antitumor immunity, Daley and colleagues assessed dectin-1 expression in tumors from transgenic mouse models of slow-growing and invasive PDAC and from human patients with PDAC. Dectin-1 was highly expressed in both murine and human patient PDAC tumors and in peritumoral leukocytes, macrophages, and monocytes; further, elevated levels of phosphorylated SYK and dectin-1 ligands were also present in murine PDAC and the inflammatory TME. Of the identified dectin-1 ligands, galectin-9 was confirmed to interact with dectin-1 and activate SYK, and was shown to be overexpressed in murine and human PDAC and tumor-infiltrating leukocytes. Treatment with a dectin-1 agonist accelerated murine PDAC progression; conversely, Clec7a ablation or the blockade of SYK or galectin-9 delayed murine PDAC progression. Specifically, Clec7a depletion in the extra-epithelial compartment, but not in transformed pancreatic epithelial cells, was protective against PDAC, and Clec7a depletion or the blockade of galectin-9 resulted in the M1 polarization of TAMs to promote the immunogenic differentiation of PDAC-infiltrating T cells in vitro and in vivo and reduce PDAC growth in vivo. These results describe how the dectin-1–galectin-9 axis drives the immunosuppressive T-cell phenotype and suggest that inhibition of dectin-1–mediated signaling is a potential immunotherapy that may synergize with other immunotherapies for the treatment of patients with PDAC.

Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med 2017;23:556–67.

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