Deciphering CD137 (4‐1BB) signaling in T‐cell costimulation for translation into successful cancer immunotherapy

Abstract

CD137 (4-1BB, TNF-receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination-mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK-cell-mediated antibodydependent cell-mediated cytotoxicity. Reportedly, anti-CD137 mAb and adoptive T-cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T-cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology. Keywords A proposed model for CD137 signaling and its regulationSignaling via CD137 proceeds from ligated molecules at the cell surface, which become cross-linked either by trimerized ligand [14] or multivalent antibodies [3] (Fig 1). CD137 has been immunoprecipitated both as a monomer and as a dimer [2]. Extracellular binding of galectin-9 to CD137 has shown to be a factor keeping preassembled CD137 complexes together [9], which are then further cross-linked by antibody or by CD137 ligand (Fig 1). Across the TNFR family, it seems that trimers are the optimal signaling complexes [15], although a role for the formation of multimers of higher order is likely. The orientation of the monomers in the assembled complexes does not appear to be relevant for signaling, since mAbs binding different distant epitopes over the molecule have been shown to induce the same functional effects [16]. Although a conformational change of CD137 in these complexes cannot be definitively ruled out, this molecular event has not been observed with other members of the TNF-TNFR family and its requirement would not be absolute. CD137 associates with the adaptors TRAF-2 and TRAF-1 in its cytoplasmic tail, resulting in coimmunoprecipitation, which is enhanced upon CD137 activation in T cells [12, 17]. TRAF-2 is expressed in resting T lymphocytes, while TRAF-1 increases its levels of expression following activation [18]. In this way, the composition of the membrane CD137-TRAF complexes changes during lymphocyte activation.Th...

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Crystal structure of m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon receptor binding

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