Opinion
Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies

https://doi.org/10.1016/j.tips.2008.05.005Get rights and content

CD137 (also known as 4-1BB) is a surface co-stimulatory glycoprotein originally described as present on activated T lymphocytes. Artificial stimulation of this molecule with monoclonal antibodies or other agonist moieties therapeutically augments the cellular immune response against tumors, regardless of the absence of CD137 on tumor cells. These pharmacological agents, when administered systemically, surpass the immune effects of the membrane-bound natural ligand (CD137 or 4-1BB ligand), the activity of which is confined to cell-to-cell interactions. Greater affinity and broader distribution of the CD137 pharmacological agonists cause much more intense receptor crosslinking and stronger intracellular signals than the natural ligand. Target engagement on a variety of immune cell types such as T, natural killer and dendritic cells and on tumor vessels could switch on multiple mechanisms of action. As an agonist, anti-CD137 monoclonal antibody has entered Phase II clinical trials; elucidation of the mechanisms behind the antitumor efficacy requires further research in mice and patients to understand and rationally combine these new treatments.

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

References (59)

  • M. Wolfl

    Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities

    Blood

    (2007)
  • Y. Zhu

    CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype

    Blood

    (2007)
  • D.S. Vinay

    Dual immunoregulatory pathways of 4-1BB signaling

    J. Mol. Med.

    (2006)
  • B.S. Kwon et al.

    cDNA sequences of two inducible T-cell genes

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • T.H. Watts

    TNF/TNFR family members in costimulation of T cell responses

    Annu. Rev. Immunol.

    (2005)
  • D. Drenkard

    CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity

    FASEB J.

    (2007)
  • I. Melero

    Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors

    Nat. Med.

    (1997)
  • Y. Sun

    Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease

    Nat. Med.

    (2002)
  • S.K. Seo

    4-1BB-mediated immunotherapy of rheumatoid arthritis

    Nat. Med.

    (2004)
  • J.O. McNamara

    Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice

    J. Clin. Invest.

    (2008)
  • I. Melero

    Immunostimulatory monoclonal antibodies for cancer therapy

    Nat. Rev. Cancer

    (2007)
  • D.H. Lynch

    The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer

    Immunol. Rev.

    (2008)
  • T. Uno

    Eradication of established tumors in mice by a combination antibody-based therapy

    Nat. Med.

    (2006)
  • D.W. McMillin

    Complete regression of large solid tumors using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy

    Hum. Gene Ther.

    (2006)
  • W. Shi et al.

    Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment

    Anticancer Res.

    (2006)
  • R.A. Wilcox

    Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors

    J. Clin. Invest.

    (2002)
  • F. Ito

    Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines

    Cancer Res.

    (2004)
  • S.J. Robertson

    CD137 costimulation of CD8+ T cells confers resistance to suppression by virus-induced regulatory T cells

    J. Immunol.

    (2008)
  • R.A. Wilcox

    Cutting edge: Expression of functional CD137 receptor by dendritic cells

    J. Immunol.

    (2002)
  • Cited by (88)

    • Adjuvants for improving cancer vaccines

      2022, Cancer Vaccines as Immunotherapy of Cancer
    • Anticalin®-based therapeutics: Expanding new frontiers in drug development

      2022, International Review of Cell and Molecular Biology
    • Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

      2021, Breast
      Citation Excerpt :

      The effect of blocking the HLA-G/KIR2DL4 interaction improves the vulnerability of HER2-positive BC to trastuzumab treatment in vivo [35]. 4-1BB, also known as CD137, is a costimulatory immune receptor, a member of the TNF receptor superfamily, predominantly expressed on activated CD4+ and CD8+ T cells, activated B cells, and NK cells [36,37]. 4-1BB plays an important role in immune response modulation and is considered a promising target for cancer immunotherapy given that it is expressed on TILs.

    View all citing articles on Scopus
    View full text