Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells

Charles Maisonneuve, Derek K.L. Tsang, Elisabeth G. Foerster, Lukian Maxence Robert, Tapas Mukherjee, Dave Prescott, Ivan Tattoli, Paul Lemire, Daniel A. Winer, Shawn Winer, Catherine J. Streutker, Kaoru Geddes, Ken Cadwell, Richard L. Ferrero, Alberto Martin, Stephen E. Girardin, Dana J. Philpott

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 demonstrate the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using a model of self-limiting peritonitis, we show that systemic Nod1 activation promotes an autophagy-dependent reprogramming of macrophages toward an alternative phenotype. Moreover, Nod1 stimulation induces the expansion of myeloid-derived suppressor cells (MDSCs) and maintains their immunosuppressive potential via arginase-1 activity. Supporting the role of MDSCs and tumor-associated macrophages in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustains 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 activity of myeloid cells and fuel tumor progression in CRC.

Original languageEnglish
Article number108677
Number of pages24
JournalCell Reports
Volume34
Issue number4
DOIs
Publication statusPublished - 26 Jan 2021

Keywords

  • arginase-1
  • Atg16L1
  • autophagy
  • colon cancer
  • immunosuppression
  • MDSC
  • microbiota
  • Nod1 receptor
  • TAM
  • TME

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