Hase-Nelson, M. (Michelle)

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    CD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
    (Nature Publishing Group, 2021) Otano, I. (Itziar); Azpilikueta, A. (Arantza); Glez-Vaz, J. (Javier); Álvarez-Rodríguez, M. (Maite); Medina-Echeverz, J. (José); Cortés-Dominguez, I. (Iván); Ortiz-de-Solorzano, C. (Carlos); Ellmark, P. (Peter); Fritzell, S. (Sara); Hernandez-Hoyos, G. (Gabriela); Hase-Nelson, M. (Michelle); Ochoa, M.C. (María Carmen); Bolaños, E. (Elixabet); Cuculescu, D. (Doina); Jauregui-Jiménez, P. (Patricia); Sánchez-Gregorio, S. (Sandra); Etxeberria, I. (Iñaki); Rodriguez-Ruiz, M.E. (María Esperanza); Fernandez-Sanmamed, M. (Miguel); Teijeira, A. (Álvaro); Berraondo, P. (Pedro); Melero, I. (Ignacio)
    CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans.