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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.

Original publication




Journal article


Nature communications

Publication Date





Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.


CD8-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Receptor-CD3 Complex, Antigen, T-Cell, Cytokines, Lymphocyte Activation, Cell Proliferation, CD3 Complex, Tumor Necrosis Factor Receptor Superfamily, Member 9