Nod1 Limits Colitis-Associated Tumorigenesis by Regulating IFN-γ Production

Abstract

Chronic intestinal inflammation is a major risk factor for the development of colorectal cancer. Nod1, a member of the Nod-like receptor (NLR) family of pattern recognition receptors, is a bacterial sensor that has been previously demonstrated to reduce susceptibility of mice to chemically-induced colitis and subsequent tumorigenesis, but the mechanism by which it mediates its protection has not been elucidated. Here, we show that Nod1 expression in the hematopoietic cell compartment is critical for limiting inflammation-induced intestinal tumorigenesis. Specifically, Nod1-deficient T cells exhibit impaired IFNγ production during dextran sulfate sodium (DSS)-induced acute inflammation in vivo, and administration of the Nod1 ligand KF1B enhances IFNγ responses by anti-CD3-activated T cells in vitro. Absence of IFNγ signaling results in increased inflammation-associated tumors in mice, and adoptive transfer of Nod1-/- or IFNγ-/- T cells into T cell-deficient mice results in increased tumorigenesis as compared to T cell-deficient mice that were adoptively transferred with WT T cells. Altogether, these results suggest a previously unappreciated role for the innate immune receptor Nod1 in suppressing colitis-associated tumorigenesis through a T cell-mediated mechanism.

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

“…21 NODs have been studied to a greater extent in cancers of the gastrointestinal tract, such as colorectal cancer (CRC) and gastric cancer (GC), although studies in breast cancer, oral squamous cell carcinoma (OSCC), head and neck squamous cell carcinoma (HNSCC), and pancreatic cancer (PC) have also been conducted ( Table 1). Stimulation of NOD1 and NOD2 was found to be protective in inflammation-induced CRC, [69][70][71]80 whereas there was no straightforward answer as to whether activation of NOD1 in the stomach promotes or prevents the development of GC. [72][73][74] Moreover, NOD1 was found to be upregulated in PC, 79 HNSCC, 77,78 OSCC, 76 and GC, 73,74 as opposed to certain studies that reported NOD1 downregulation in the cases of OSCC 75 and GC.…”

“…NOD1 deficiency in T cells is associated with impaired IFN-γ production and STAT1 activation. 70 NOD2 P NOD2 (or RIPK2) deficiency results in increased susceptibility to tumor formation in AOM/DSS mouse model of colon cancer. Absence of NOD2 (or RIPK2) promotes pro-inflammatory microenvironment in the intestines leading to enhanced epithelial dysplasia following chemically induced injury.…”

NOD1 and NOD2 in inflammatory and infectious diseases

“…NOD1 and NOD2 are also expressed in B and T cells, although level of expression is dependent on cellular location. There are some data to suggest that NOD1 and NOD2 ligands can enhance B and T cells after B‐cell receptor (BCR) and T‐cell receptor (TCR) engagement 105‐107 . Specifically, in human tonsillar B cells, NOD1 or NOD2 activation alone by treatment with their respective ligands was insufficient to trigger B cell activation or proliferation whereas the combination of NOD1 and NOD2 ligands and BCR activation via IgM or IgD stimulation resulted in enhanced cellular proliferation in vitro, which is further augmented by concomitant TLR stimulation 105 .…”

“…Nonetheless, in mixed cultures of tonsillar mononuclear cells, enhanced cellular proliferation of T cells was observed after anti‐CD3/CD28 stimulation together with NOD1/NOD2 agonists although the effect was relatively weak 106 . With purified murine splenic CD3 + T cells, it was also demonstrated that NOD1 ligand can act as a co‐stimulatory molecule to enhance IFN‐γ production after stimulation with anti‐CD3 alone; however, the possibility of a contributing factor by potential contaminating antigen‐presenting cells was not ruled out 107 . Regardless, as these studies were all performed in vitro, the physiologic significance of these findings remains to be determined in vivo.…”

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“…The mechanisms through NLR-mediated effects are associated with increased CRC risk relates mainly to an excessive NLR-induced chronic pro-inflammatory microenvironment [142]. Intriguingly, NLR agonists, specially NOD1 and NOD2 agonists, have been proposed as therapeutic agents in CRC treatment because both experimental studies showed that NOD1 deficiency leads to increased tumorigenesis in mice [143] and the activation of these NLR may regulate the proinflammatory effects induced by other PRR [144,145]. Thus, although both beneficial and deleterious effects of NLR activation on CRC remains not fully understood, it seems that punctual activation or inhibition of NLR could differentially induce effects during cancer development, progression, and metastasis.…”