Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology

Abstract

Tumor necrosis factor α (TNF) is a potent pro-inflammatory cytokine that has deleterious effect in some autoimmune diseases, which led to the use of anti-TNF drugs in some of these diseases. However, some rare patients treated with these drugs paradoxically develop an aggravation of their disease or new onset autoimmunity, revealing an immunosuppressive facet of TNF. A possible mechanism of this observation is the direct and positive effect of TNF on regulatory T cells (Tregs) through its binding to the TNF receptor type 2 (TNFR2). Indeed, TNF is able to increase expansion, stability, and possibly function of Tregs via TNFR2. In this review, we discuss the role of TNF in graft-versus-host disease as an example of the ambivalence of this cytokine in the pathophysiology of an immunopathology, highlighting the therapeutic potential of triggering TNFR2 to boost Treg expansion. We also describe new targets in immunotherapy of cancer, emphasizing on the putative suppressive effect of TNF in antitumor immunity and of the interest of blocking TNFR2 to regulate the Treg compartment.

M2b macrophage polarization and its roles in diseases

“…TNF‐α, a pleiotropic mediator, is central to host defense and inflammatory responses by binding its receptors (TNFR1 and TNFR2) . Initially, TNF‐α was considered as a proinflammatory cytokine.…”

“…Initially, TNF‐α was considered as a proinflammatory cytokine. However, later preclinical and clinical studies have shown that it also mediates a paradoxical anti‐inflammatory and immune‐modulatory effect . Its pleiotropic effects often lead to opposing outcomes during the development of immune‐mediated diseases .…”

“…Its pleiotropic effects often lead to opposing outcomes during the development of immune‐mediated diseases . Although it can be produced by many other cell types such as neutrophils, lymphocytes, NK cells, and mast cells, TNF‐α is chiefly produced by activated macrophages . In activated macrophages, M1 and M2b are the main cell types expressing and secreting TNF‐α .…”

“…TNF-, a pleiotropic mediator, is central to host defense and inflammatory responses by binding its receptors (TNFR1 and TNFR2). 72 Initially, TNF-was considered as a proinflammatory cytokine. However, later preclinical and clinical studies have shown that it also mediates a paradoxical anti-inflammatory and immune-modulatory effect.…”

“…However, later preclinical and clinical studies have shown that it also mediates a paradoxical anti-inflammatory and immune-modulatory effect. 72,73 Its pleiotropic effects often lead to opposing outcomes during the development of immune-mediated diseases. 74 Although it can be produced by many other cell types such as neutrophils, lymphocytes, NK cells, and mast cells, TNF-is chiefly produced by activated macrophages.…”