The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.

Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor α Induce Antigen-specific Protection of Mice from Autoimmunity

10.1084/jem.20011341 ◽

2001 ◽

Vol 195 (1) ◽

pp. 15-22 ◽

Cited By ~ 388

Author(s):

Mauritius Menges ◽

Susanne Rößner ◽

Constanze Voigtländer ◽

Heike Schindler ◽

Nicole A. Kukutsch ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Cell Immunity ◽

Tnf Α ◽

Factor Α ◽

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.

Tumor Necrosis Factor Receptor-1 (p55) Deficiency Attenuates Tumor Growth and Intratumoral Angiogenesis and Stimulates CD8+ T Cell Function in Melanoma

Cells ◽

10.3390/cells9112469 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2469

Author(s):

Yamila I. Rodriguez ◽

Ludmila E. Campos ◽

Melina G. Castro ◽

Nadia Bannoud ◽

Ada G. Blidner ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Tumor Cell ◽

Cd8 T Cells ◽

Tumor Necrosis ◽

Cd8 T Cell ◽

Tnf Α ◽

The Impact ◽

The role of tumor necrosis factor-α (TNF-α) in shaping the tumor microenvironment is ambiguous. Consistent with its uncertain role in melanoma, TNF-α plays a dual role, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. TNF-α signals via two cognate receptors, namely TNFR1 (p55) and TNFR2 (p75), which mediate divergent biological activities. Here, we analyzed the impact of TNFR1 deficiency in tumor progression in the B16.F1 melanoma model. Tumors developed in mice lacking TNFR1 (TNFR1 knock-out; KO) were smaller and displayed lower proliferation compared to their wild type (WT) counterpart. Moreover, TNFR1 KO mice showed reduced tumor angiogenesis. Although no evidence of spontaneous metastases was observed, conditioned media obtained from TNFR1 KO tumors increased tumor cell migration. Whereas the analysis of tumor-associated immune cell infiltrates showed similar frequency of total and M2-polarized tumor-associated macrophages (TAMs), the percentage of CD8+ T cells was augmented in TNFR1 KO tumors. Indeed, functional ex vivo assays demonstrated that CD8+ T cells obtained from TNFR1KO mice displayed an increased cytotoxic function. Thus, lack of TNFR1 attenuates melanoma growth by modulating tumor cell proliferation, migration, angiogenesis and CD8+ T cell accumulation and activation, suggesting that interruption of TNF-TNFR1 signaling may contribute to control tumor burden.

Function of CD4+CD3− cells in relation to B- and T-zone stroma in spleen

Blood ◽

10.1182/blood-2006-04-018465 ◽

2006 ◽

Vol 109 (4) ◽

pp. 1602-1610 ◽

Cited By ~ 69

Author(s):

Mi-Yeon Kim ◽

Fiona M. McConnell ◽

Fabrina M. C. Gaspal ◽

Andrea White ◽

Stephanie H. Glanville ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Stromal Cells ◽

Tumor Necrosis ◽

Accessory Cell ◽

Segregation Process ◽

Tnf Α ◽

Deficient Mice ◽

Abstract Lymphocytes from lymphotoxin (LT) α–deficient mice, which lack segregation of their B- and T-cell areas, acquire normal organization following adoptive transfer into RAG-deficient recipients, identifying a non-B non-T cell in the segregation process. Here we show that a CD4+CD3− accessory cell is tightly associated with discrete VCAM-1–expressing stromal cells in B- and T-cell areas of the mouse spleen. CD4+CD3− cells express high levels of LTα, LTβ, and tumor necrosis factor (TNF) α, which are the ligands for the LTβ receptor and TNFR1 expressed by stromal cells. The expression of these ligands is functional, as transferring CD4+CD3− cells derived from either embryonic or adult tissues into LTα-deficient mice organizes B/T segregation and up-regulates CCL21 protein expression in areas where T cells are segregated from B cells. We propose that the function of CD4+CD3− cells is to form a link between primed CD4 T cells and the underlying stromal elements, creating distinct microenvironments in which they enable effector responses.

Functional characterization of the human tumor necrosis factor receptor p75 in a transfected rat/mouse T cell hybridoma.

10.1084/jem.176.4.1015 ◽

1992 ◽

Vol 176 (4) ◽

pp. 1015-1024 ◽

Cited By ~ 80

Author(s):

P Vandenabeele ◽

W Declercq ◽

D Vercammen ◽

M Van de Craen ◽

J Grooten ◽

...

Keyword(s):

T Cells ◽

Biological Activity ◽

T Cell ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Functional Characterization ◽

Human Tumor ◽

Human Tumor Necrosis Factor ◽

We investigated the biological role of the human tumor necrosis factor p75 (hTNF-R75), making use of the species specificity of TNF responses in murine (m) T cell lines. Several TNF-mediated activities on mouse T cells, such as cytokine induction or proliferation, showed a 100-500-fold difference in specific biological activity between mTNF and hTNF. After transfection of hTNF-R75 cDNA in a rat/mouse T cell hybridoma (PC60), however, the 100-fold lower specific biological activity of hTNF was converted to the same specific biological activity as mTNF. The TNF-mediated induction of granulocyte/macrophage colony-stimulating factor was strongly synergized by the addition of interleukin 1. In the presence of the latter cytokine, ligand-competing monoclonal antibodies against hTNF-R75 (utr-1, utr-2, utr-3) were agonistic on transfected PC60 cells. This agonistic activity was further enhanced by crosslinking with sheep anti-murine immunoglobulin antibodies. These data provide direct evidence for a functional role of TNF-R75, without ligand-dependent TNF-R55 involvement, in the induction of cytokine secretion in T cells.

Nonlymphocyte-Derived Tumor Necrosis Factor Is Required for Induction of Colitis in Recombination Activating Gene (Rag)2−/− Mice upon Transfer of Cd4+Cd45rbhi T Cells

10.1084/jem.190.10.1479 ◽

1999 ◽

Vol 190 (10) ◽

pp. 1479-1492 ◽

Cited By ~ 97

Author(s):

Nadia Corazza ◽

Susanne Eichenberger ◽

Hans-Pietro Eugster ◽

Christoph Mueller

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Colonic Mucosa ◽

Clinical Signs ◽

Interferon Γ ◽

Tnf Α ◽

Recombination Activating Gene ◽

In this study, we addressed the role of tumor necrosis factor (TNF)-α and lymphotoxin (LT)-α in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-α and LT-α) relevant to disease development. After adoptive transfer of TNF+/+ CD4+CD45RBhi splenocytes into TNF+/+ recombination activating gene (RAG)2−/− mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF−/−RAG2−/− recipients of TNF−/− CD4+CD45RBhi T cells, although elevated numbers of interferon-γ–producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF−/−CD4+CD45RBhi T cells into TNF+/+RAG2−/− recipients, colitis develops with kinetics similar to those upon transfer of TNF+/+CD4+CD45RBhi donor cells. In contrast, no clinical signs of colitis are observed in TNF−/−RAG2−/− recipients of TNF+/+CD4+CD45RBhi T cells. This protection from colitis is not a consequence of the absence of LT-α, as TNF-α−/−RAG2−/− recipients of TNF-α−/− CD4+CD45RBhi T cells are also protected from colitis induction. These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-α in this mouse model of colitis.

Role of tumor necrosis factor-α in the regulation of activated synovial T cell growth: Downregulation of synovial T cells in rheumatoid arthritis patients

European Journal of Immunology ◽

10.1002/eji.1830251207 ◽

1995 ◽

Vol 25 (12) ◽

pp. 3243-3248 ◽

Cited By ~ 5

Author(s):

Ning-Sheng Lai ◽

Joung-Liang Lan ◽

Chia-Li Yu ◽

Rong-Hwa Lin

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

Cell Growth ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Factor Α ◽

T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor.

10.1084/jem.175.1.91 ◽

1992 ◽

Vol 175 (1) ◽

pp. 91-98 ◽

Cited By ~ 390

Author(s):

T Miethke ◽

C Wahl ◽

K Heeg ◽

B Echtenacher ◽

P H Krammer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Staphylococcal Enterotoxin B ◽

Toxic Shock ◽

Lethal Shock ◽

Enterotoxin B ◽

Because mice are more resistant than humans to the pathogenic effects of bacterial toxins, we used D-Galactosamine- (D-Gal) sensitized mice as a model system to evaluate potential toxic shock symptoms triggered by the superantigen staphylococcal enterotoxin B (SEB). We show that similar to endotoxin (lipopolysaccharide) [LPS], the exotoxin SEB causes lethal shock within 8 h in D-Gal-sensitized mice, inducing 100% and about 50% lethality with 20 and 2 micrograms SEB, respectively. The lethal shock triggered by the superantigen SEB is mediated by T cells, a conclusion based on the observation that T cell repopulation of SCID mice conferred sensitivity to SEB. Since CSA also conferred protection, the role of T cell-derived lymphokines in mediating lethal shock was evaluated. Within 30-60 min after SEB injection, serum tumor necrosis factor (TNF) levels peaked, followed immediately by interleukin-2 (IL-2). Serum-borne lymphokines were detected well in advance of signs of T cell activation, as assessed by IL-2 receptor expression of SEB-reactive V beta 8+ T cells. Passive immunization with anti-TNF-alpha/beta-neutralizing monoclonal antibody also conferred protection, indicating that it is TNF which is critical for initiating toxic shock symptoms. Taken together, this study defines basic differences between endotoxin (LPS)- and exotoxin (SEB)-mediated lethal shock, in that the former is mediated by macrophages and the latter by T cells. Yet the pathogenesis distal to the lymphokine/cytokine-producing cells appears surprisingly similar in that TNF represents a key mediator in inducing shock.

Abstract 1208: Deficiency of Interleukin-1 receptor antagonist in T cells promotes Aortic Valve Stenosis by releasing Tumor Necrosis Factor-α

Circulation ◽

10.1161/circ.116.suppl_16.ii_245-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Kikuo Isoda ◽

Taizo Matsuki ◽

Tomiharu Niida ◽

Norio Ishigami ◽

Harumi Kondo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Aortic Valve ◽

Receptor Antagonist ◽

Tumor Necrosis ◽

Valve Leaflet ◽

Aortic Valve Leaflet ◽

Tnf Α ◽

The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via IL-1 receptor antagonist (IL-1Ra). We have shown that IL-1Ra-deficient (IL-1Ra −/− ) mice develop degenerative aortic valve stenosis (AS) that is the most common valvular disease in Western countries. The objective of this study is to determine the mechanisms by which deficiency of IL-1Ra may promote AS. Method and Results : IL-1Ra −/− mice (backcrossed 8 generations to the BALB/c background) and wild-type (WT) mice did not differ with regard to body weight, heart weight, and systolic arterial pressure. Furthermore, no significant differences in plasma lipid levels were observed between IL-1Ra −/− and WT mice. However histological analysis revealed that IL-1Ra −/− mice developed aortitis and showed increased aortic valve leaflet thickness compared to WT mice at the age of 12 weeks (p<0.001). Echo cardiograms also revealed that IL-1Ra −/− mice displayed higher transvalvular velocities than WT mice at the age of 40 weeks (p<0.01). These findings showed that IL-1Ra−/− mice spontaneously developed AS. In this study, we examined the role of T cells in development of AS by peripheral T cell transplantation. Transplantation of T cells from WT mice induced mild swelling of aortic valve leaflet in nu/nu mice. In contrast, T cells from IL-1Ra −/− mice induced an increase in aortic valve thickness in nu/nu mice. We next checked T cell function. After anti-CD3 antibody stimulation, IL-1Ra −/− T cells produced much higher levels of tumor necrosis factor (TNF)-α in culture supernatants compared to those from WT mice (p<0.001). Furthermore, in IL-1Ra −/− mice, TNF-α protein levels were higher than in WT mice (106.2±12.5 vs. 216.5±12.5 pg/mL, p<0.001) in vivo. Finally, we studied the roles of TNF-α in the development of AS in IL-1Ra −/− mice by generating double gene deficient (TNF-α −/− / IL-1Ra −/− ) mice. Interestingly, TNF-α −/− /IL-1Ra −/− mice did not develop AS. Conclusions : These findings suggest that IL-1Ra deficiency in T cells disrupts homeostasis of the immune system and TNF-α plays an important role in the development of AS in IL-1Ra −/− mice. These novel findings provide a clue for the development of new therapies for AS.