NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis.

The innate immune protein NLRC5 plays a key role in cancer immune surveillance. Reduced NLRC5 expression is associated with a poor prognosis for many types of cancers. Previously, we showed that mice with a myeloid-specific deletion of Nlrc5 (Nlrc5mø-KO) develop gastric lymphoid lesions to Helicobacter infection resembling early-stage marginal zone lymphoma. We hypothesized that NLRC5 deficiency may promote a tumor-permissive microenvironment mediated by tumor-associated macrophages (TAMs). Consistent with this hypothesis, splenic macrophages from Helicobacter-infected Nlrc5mø-KO mice had upregulated expression of genes encoding the TAM receptor tyrosine kinases, Axl and Mertk. The levels of AXL and MERTK gene expression and MERTK phosphorylation were increased in NLRC5-/- THP-1 macrophages when compared with WT cells. In response to Helicobacter stimulation, Nlrc5-/- macrophages had significantly elevated anti-inflammatory responses (IL-10, TGF-β, Socs1, Socs3) compared with WT cells. Importantly, Nlrc5-/-macrophages showed enhanced efferocytosis and reduced antigen presentation to CD8+ T cells. Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection.