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

ABSTRACT

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 ( Nlrc5 ^mø‐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 Nlrc5 ^mø‐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.