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. 2013 Mar 1;19(5):1044-53.
doi: 10.1158/1078-0432.CCR-12-2065.

Agonist antibodies to TNFR molecules that costimulate T and NK cells

Ignacio Melero  1 , Daniel Hirschhorn-Cymerman, Aizea Morales-Kastresana, Miguel F Sanmamed, Jedd D Wolchok
Affiliations

Agonist antibodies to TNFR molecules that costimulate T and NK cells

Ignacio Melero et al. Clin Cancer Res. .

Erratum in

  • Clin Cancer Res. 2013 Apr 1;19(7):1913

Abstract

Therapy for cancer can be achieved by artificially stimulating antitumor T and natural killer (NK) lymphocytes with agonist monoclonal antibodies (mAb). T and NK cells express several members of the TNF receptor (TNFR) family specialized in delivering a costimulatory signal on their surface. Engagement of these receptors is typically associated with proliferation, elevated effector functions, resistance to apoptosis, and differentiation into memory cells. These receptors lack any intrinsic enzymatic activity and their signal transduction relies on associations with TNFR-associated factor (TRAF) adaptor proteins. Stimulation of CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNFR (GITR; CD357) promotes impressive tumor-rejecting immunity in a variety of murine tumor models. The mechanisms of action depend on a complex interplay of CTL, T-helper cells, regulatory T cells, dendritic cells, and vascular endothelium in tumors. Agonist mAbs specific for CD137 have shown signs of objective clinical activity in patients with metastatic melanoma, whereas anti-OX40 and anti-GITR mAbs have entered clinical trials. Preclinical evidence suggests that engaging TNFR members would be particularly active with conventional cancer therapies and additional immunotherapeutic approaches. Indeed, T-cell responses elicited to tumor antigens by means of immunogenic tumor cell death are amplified by these immunostimulatory agonist mAbs. Furthermore, anti-CD137 mAbs have been shown to enhance NK-mediated cytotoxicity elicited by rituximab and trastuzumab. Combinations with other immunomodulatory mAb that block T-cell checkpoint blockade receptors such as CTLA-4 and PD-1 are also promising.

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Figures

Figure 1
Figure 1. Cell surface-attached costimulatory members of the TNF and TNFR superfamilies
Schematic receptor-ligand pair interactions of the costimulatory members of the TNF and TNFR families at immune synapses. Receptors are color-coded for activation-dependent inducibility and the family of molecules is shape-coded. Plus (+), minus (-) and question mark (?) signs placed at the side of the arrows indicate activatory and inhibitory signals or unknown functional effects. The TNF family with at least 18 described members and TNFR family that encompass at least 27 members play functions in many other biological functions beyond costimulation (Table 1) of T and NK responses. It is well known that some of the TNF members act as cell surface-attached molecules and some as soluble cytokines that in some cases can hetero trimerize. Soluble forms of the costimulatory members depicted in the figure have been described but their functional importance remains elusive. We can classify TNFR family members depending on the presence absence of a death domain in the cytoplasmic tail. This death domain recruits apoptosis inducing molecules upon ligation of the receptor and is absent from the costimulatory members whose main function is to convey proinflamatory and activatory signals. The pair CD40/CD40 ligand has not been included since the main role of CD40 is activating antigen-presenting cells and has been reviewed in detail in an accompanying review (100).
Figure 2
Figure 2. Early signal transduction events from CD137
Schematic representation of TRAF-2 and TRAF-1 recruitment by CD137 surface molecules perturbed by the natural ligand or agonist mAb. TRAF-2 has associated ubiquitin ligase activity (E3) that dictate self ubiquitination and presumably ubiquitination of other protein targets. These events lead to recruitment of TAB1/2-TAK1 complexes that downstream activate NF-κB and MAP-Kinases. Signals controlled or modulated by TRAF-1 are less well understood. K63 polyubiquitin chains are removed by deubiquitinases (i.e: CYLD and A20) which keep the pathway under control and therefore offer potential therapeutic targets.
Figure 3
Figure 3. Schematic representation of the sites and cells on which agonist anti-CD137 mAbs act as example of TNFR mAb mechanism
The main mechanism of action is costimulation of CD8+ CTLs crossprimed by DC against tumor antigens. CD137 expression on dendritic cells, activated CD4 T cells (including Tregs) and on tumor blood and lymphatic vessels could offer additional sites and mechanisms of action. Similar mode of action settings can be envisioned for other TNFR members suitable for targeted cancer immunotherapy.
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