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Abstract 1691: CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation

2021; American Association for Cancer Research; Volume: 81; Issue: 13_Supplement Linguagem: Inglês

10.1158/1538-7445.am2021-1691

1538-7445

Itziar Otano, Arantza Azpilikueta, Javier Glez‐Vaz, Peter Ellmark, Sara Fritzell, Gabriela Fernandez-Hoyos, Michelle H. Nelson, Maite Álvarez, María del Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jáuregui, Sandra Sánchez, Iñaki Etxeberría, María E. Rodríguez-Ruiz, Miguel F. Sanmamed, Álvaro Teijeira, Pedro Berraondo, Igancio Melero,

Cancer Immunotherapy and Biomarkers

Abstract CD137 (4-1BB, TNFSFR9) costimulation provides antigen-primed T cells with increased survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being harnessed 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 cells is far superior to that provided in-trans in terms of T-cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mice and humans. 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. 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 provide costimulation either in cis or in trans. Citation Format: Itziar Otano, Arantza Azpilikueta, Javier Glez-Vaz, Peter Ellmark, Sara Fritzell, Gabriela Fernandez-Hoyos, Michelle Hase Nelson, Maite Alvarez, María del Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jauregui, Sandra Sanchez, Iñaki Etxeberría, María E. Rodriguez-Ruiz, Miguel F. Sanmamed, Alvaro Teijeira, Pedro Berraondo, Igancio Melero. CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1691.