Nod1 Promotes Colorectal Carcinogenesis by Regulating the Immunosuppressive Functions of Tumor-Infiltrating Myeloid Cells

Abstract

Summary Pioneering studies from the early 1980s suggested that bacterial peptidoglycan-derived muramyl peptides (MPs) could exert either stimulatory or immunosuppressive functions depending, in part, on chronicity of exposure. However, this Janus-faced property of MPs remains largely unexplored. Here, we investigated the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using first a model of self-limiting peritonitis, we show that systemic Nod1 activation promoted an autophagy-dependent reprogramming of macrophages towards an alternative phenotype. Moreover, Nod1 stimulation induced the expansion of myeloid-derived suppressor cells (MDSCs) and maintained their immunosuppressive potential via Arginase-1 activity. Supporting the role of MDSCs in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustained intra-tumoral Arginase-1 levels to foster an immunosuppressive and tumor-permissive microenvironment during colorectal cancer (CRC) development. Our findings support the notion that bacterial products, via Nod1 detection, modulate the immunosuppressive potential of myeloid cells, which ultimately and inadvertently fuels tumor progression in CRC.