Trends in Pharmacological Sciences
OpinionMulti-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies
Introduction
CD137 (also known as 4-1BB) is a surface glycoprotein that belongs to the tumor necrosis factor (TNF)-receptor family (see Glossary) and was discovered as a mRNA selectively expressed in activated, but not in resting, T lymphocytes 1, 2 (Figure 1). Multiple studies have defined CD137 as a co-stimulatory molecule for T-cell activation [1]. CD137 is activated by CD137 ligand (CD137L or 4-1BBL), a transmembrane molecule of the TNF family that is expressed on activated macrophages, B cells and dendritic cells or with agonist monoclonal antibodies (mAbs) [3]. Interestingly, CD137L has been recently found to send reverse signals to the antigen-presenting cells upon CD137 engagement [4] (Figure 1). In vitro, CD137 stimulation complements the activation elicited by the T-cell antigen receptor (TCR) resulting in enhancement of proliferation, survival and effector functions such as cytotoxicity and cytokine secretion 1, 3. Antibodies that activate CD137 function cure various mouse tumors by enhancing the antitumor immune response that is mainly mediated by cytolytic T lymphocytes (CTLs) [5] (Box 1). Intriguingly, the same agents ameliorate or prevent autoimmunity in mouse models mainly via interference with autoreactive CD4 T cells 6, 7, 8. In addition to agonist mAbs, other CD137-binding molecules such as recombinant proteins containing the binding domain of CD137L or RNA-dimerized aptamers can function as agonists [9]. The agonist human anti-CD137 mAb is currently in Phase I and II clinical trials for the treatment of several solid tumors 10, 11. It is exciting that, in rodent cancer models, combinations of anti-CD137 mAbs with multiple experimental [12] or approved cancer treatments (including conventional chemotherapy and radiotherapy) 13, 14 result in marked synergistic effects and provide the basis for promising clinical trials [10].
The sequence of events accounting for the mechanisms of action of agonist CD137 mAbs in antitumor therapy was originally postulated as follows [5]: T cells are stimulated by tumor antigens and TCR-stimulated T cells upregulate CD137. The anti-CD137 agonist mAb, administered systemically, co-stimulates the T cells that have upregulated CD137, and CD137 then delivers signals that prevent apoptosis and promote effector functions of antitumor CTLs [1].
The fact that vaccines with tumor antigens that are recognized by CD8 T cells synergize with anti-CD137 mAb indicates that antigen presentation might be a limiting factor 15, 16, 17. Moreover, CD137 attains unprecedented efficacy when endogenous antigen presentation is enhanced by simultaneous promotion of tumor-cell apoptosis and maturation of antigen-presenting dendritic cells [12] (Box 1).
This described sequence of cellular events has been confirmed in multiple mouse experiments but, based on the cellular expression of CD137, it is likely that other immune-mediated antitumor mechanisms might be induced. Other members of the TNF receptor superfamily can be targeted to elicit antitumor effects. This has been observed in the case of CD40, glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40 (also known as CD134), CD27 and herpes virus entry mediator (HVEM) 3, 10. Various immune mechanisms have been proposed that include (i) activation of antigen-presenting cells, (ii) deactivation of regulatory cells (Tregs) or making effector T cells insensitive to the inhibition mediated by regulatory T cells [18], and (iii) co-stimulation of effector CD4 and CD8 T cells 3, 10. These three types of mechanisms can be set in motion, or at least augmented, by CD137-receptor stimulation 19, 20, 21. Although it is assumed that the co-stimulation of CD8 T cells is the principal mechanism of action, additional mechanisms can become crucial when the tumor shows low immunogenicity.
Section snippets
CD137: the possible roles of signaling and internalization after pharmacological stimulation with mAbs
Activation of other members of the TNF receptor family involves trimerization by the ligand, and signaling occurs after receptor multimerization events 3, 22, 23. Crosslinking with bivalent high-affinity antibodies is an overtly supraphysiological stimulus, giving rise to the crosslinking of multiple molecules. Bivalent mAbs can form multimers because some of the CD137 molecules reportedly exist as baseline homodimers [24] (Figure 1). Formation of heteromultimers with other members of the TNF
Which cells sense the agonist anti-CD137 mAb: CTLs but not only CTLs
CD137 is not restricted to activated conventional T cells. Its function on other leukocytes could be as important (Figure 3a). In the case of natural killer (NK) cells, it has been found that their depletion abrogates CD137-mediated tumor eradication in various but, importantly, not all transplanted tumor models 33, 34, 35. It is still unknown whether the function of the CD137 molecule on these cells is required for the antitumor activities of anti-CD137 mAbs. Indeed, experiments combining NK
The biology of CD137 provides insight into additional mechanisms of action
The fact that multiple cell types can be affected by CD137 agonists indicates that multiple functions are modified – as if many buttons were being hit with one finger. Here, we propose several additional mechanisms of action that might underlie the antitumor effect in addition to those classically accepted:
- (i)
Activation of the innate immune system produces an early wave of cytokines and inflammation. According to this idea, CD137 should be induced on NK cells by events dependent on the presence of
Conflict-of-interest statement
I.M. has received consulting honoraria from Bristol Myers Squibb (BMS) and Pfizer.
Acknowledgements
We are grateful to Jure-Kunkel, Feltquate and Raventos-Suarez (BMS, Princeton, NJ, USA) and Prieto and Azpilikueta (CIMA, Pamplona, Spain) for extensive scientific discussion and critical reading. Grant Support was from Ministerio de educacion y ciencia (SAF2005–03131), Departamento de Educación del Gobierno de Navarra, Departamento de Salud del Gobierno de Navarra (Beca Ortiz de Landázuri), Redes temáticas de investigación cooperativa RETIC (RD06/0020/0065), European commission VII famework
Glossary
- Bivalent mAb
- mAbs of the IgG subclass have only two antigen-binding sites that are specific for a single epitope. If directed to a membrane protein without repetitive sequences, they can crosslink homodimers but not higher-order multimers. However, if at least part of the antigens is already forming homodimers then monoclonal antibodies can multimerize the receptor.
- Co-stimulation
- antigen recognition by the TCR provides a crucial signal for the activation of T cells. TCR signals are complemented
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