Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells

Autor: Jesus Corria-Osorio, Santiago J. Carmona, Evangelos Stefanidis, Massimo Andreatta, Yaquelin Ortiz-Miranda, Tania Muller, Ioanna A. Rota, Isaac Crespo, Bili Seijo, Wilson Castro, Cristina Jimenez-Luna, Leonardo Scarpellino, Catherine Ronet, Aodrenn Spill, Evripidis Lanitis, Pedro Romero, Sanjiv A. Luther, Melita Irving, George Coukos
Rok vydání: 2023
Předmět:
Zdroj: Nature Immunology. 24:869-883
ISSN: 1529-2916
1529-2908
Popis: To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led—in the absence of lymphodepletion or exogenous cytokine support—to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.
Databáze: OpenAIRE
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