7.1.7　TNF-α

TNF-α is a pro-inflammatory cytokine produced mainly by myeloid-derived cells such as monocytes, macrophages and DCs, although many other cells such as T lymphocytes, endothelial cells, adipocytes and fibroblasts can also produce this cytokine under stressful conditions.TNF-α is recognized by two receptors with a broad tissue distribution: TNFR1 and TNFR2.TNF-α is a key pathogenic mediator of several autoimmune diseases such as rheumatoid arthritis, Crohn’s disease,ulcerative colitis, psoriasis, psoriatic arthritis and ankylosing spondylitis.TNFα activates macrophages at the inflammation site inducing the release of other pro-inflammatory cytokines that exacerbate inflammation.The activity of TNF-α on epithelial cells impairs barrier function and promotes permeability to commensal bacteria.The activity of TNF-α on fibroblasts leads to the expression of metalloproteinases and the synthesis of collagen, thereby promoting tissue fibrosis.Finally, TNF-α acts on endothelial cells to increase the adhesion molecules expressed on blood vessels, subsequently leading to increases in leucocyte infiltration; it might also induce endothelial cell apoptosis.

The relevance of this cytokine in autoimmune diseases led to the generation and approval of several TNF-α antagonists such as infliximab, adalimumab and etanercept.Infliximab is also included in the guidelines for the treatment of several autoimmune-like syndromes that are associated with immune checkpoint inhibitor treatment that are refractory to corticosteroid treatment.(https://www.daowen.com)

In cancer immunotherapy, TNF-α is mainly considered as a mediator of anti-tumor immune responses, and several immunotherapies have shown depleted anti-tumor efficacy when co-administered with TNF-α antagonists.It is likely that acute immune responses are boosted by TNF-α release.However, chronic exposure to TNF-α can promote tumor growth by mediating activation-induced cell death of effector T lymphocytes.In mouse models, TNF-α has been shown to have a detrimental effect on immunotherapies based on the blockade of the PD-1 pathway.The proposed mechanism involves the TNF-αmediated upregulation of the secondary checkpoint component TIM-3 in CD8+T lymphocytes, induced by anti-PD-1 antibody therapy.Safety of the triple combination of ipilimumab, nivolumab and an antibody to block TNF-α (infliximab or certolizumab) is being evaluated in a phase I clinical trial (NCT03293784) [2,3].