CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

Abstract

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137’s cytoplasmic tail.

ABIN1 is a negative regulator of effector functions in cytotoxic T cells

“…We speculate that the recruitment of LUBAC, which generates linear polyubiquitin chains linear polyubiquitin chains and activates NEMO to trigger downstream NF-κB activation, is a common mechanism of signaling of T-cell co-stimulation receptors from the TNFR superfamily [25]. The recent report analyzed the SC of CD137 to find components largely overlapping with our detection of the GITR SC (LUBAC, cIAP2, TRAF1, TRAF2, A20) [6]. Although the LUBAC complex was present in the SC of CD137, the authors did not detect ABIN1 [6], presumably because of technical reasons.…”

“…The recent report analyzed the SC of CD137 to find components largely overlapping with our detection of the GITR SC (LUBAC, cIAP2, TRAF1, TRAF2, A20) [6]. Although the LUBAC complex was present in the SC of CD137, the authors did not detect ABIN1 [6], presumably because of technical reasons. Recently, ABIN1 was reported to interact with the CARD11-CBM complex upon TCR signaling and to inhibit the TCR-induced NFκB activation in a human T-cell line [15], indicating that ABIN1 regulates antigenic as well as co-stimulation signaling in T cells.…”

“…LUBAC is a signal transducer in TNFR1 and MYD88 signaling [24]. Recently, LUBAC subunits were identified in the SC of CD137 TNFR superfamily receptor [6], but its involvement in GITR signaling was not shown before. We speculate that the recruitment of LUBAC, which generates linear polyubiquitin chains linear polyubiquitin chains and activates NEMO to trigger downstream NF-κB activation, is a common mechanism of signaling of T-cell co-stimulation receptors from the TNFR superfamily [25].…”

“…2) For ions with intensity in the range from 7×10 3 to 9×10 4 with CID fragmentation (35% collision energy) and 100 ms of ion injection time. 3) For ions with intensity in the range from 9×10 4 to 5×10 6 with HCD fragmentation (30% collision energy) and 100 ms of ion injection time. 4) For intensities 5×10 6 and more with HCD fragmentation (30% collision energy) and the selected precursor and its isotopes.…”

“…As these receptors enhance T-cell responses [1], some of them are used as targets of emerging anti-tumor immunotherapies [2][3][4][5]. However, despite the recent progress in uncovering the CD137 signalosome [6], the mechanisms of signal transduction of these co-stimulation TNFR superfamily receptors are still incompletely understood. A20-binding inhibitor of NFκB 1 (ABIN1 alias TNIP1) is an adaptor protein interacting with polyubiquitin signaling chains, NF-kappa-B essential modulator (NEMO), and a deubiquitinase, A20 [7].…”