NOD2 activation enhances macrophage Fcγ receptor function and may increase the efficacy of antibody therapy

Front Immunol. 2024 Jun 11:15:1409333. doi: 10.3389/fimmu.2024.1409333. eCollection 2024.

Abstract

Introduction: Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored.

Methods: Primary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.

Results: Treatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.

Conclusions: Taken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.

Keywords: NOD2 agonists; antibody-mediated responses; chronic lymphocytic leukemia; monocytes; pre-clinical model.

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
  • Animals
  • Female
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell* / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell* / metabolism
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nod2 Signaling Adaptor Protein* / agonists
  • Nod2 Signaling Adaptor Protein* / immunology
  • Nod2 Signaling Adaptor Protein* / metabolism
  • Phagocytosis
  • Receptors, IgG* / immunology
  • Receptors, IgG* / metabolism
  • Rituximab / pharmacology
  • Rituximab / therapeutic use
  • Signal Transduction

Substances

  • Nod2 Signaling Adaptor Protein
  • Receptors, IgG
  • NOD2 protein, human
  • Acetylmuramyl-Alanyl-Isoglutamine
  • Rituximab

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by R01 CA203584 (ST, JPB), K01 DK128379 (JR-R), P30 CA016058 (OSUCCC shared resources) and startup funding from The Ohio State University Comprehensive Cancer Center (JPB). This work was supported by the Pelotonia Scholars Program (MFB). Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the Pelotonia Scholars Program or The Ohio State University.