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Orthogonal Gene Engineering Enables Novel Synthetic States of Powerful Tumor-rejecting CD8+ T Cells Escaping Canonical Exhaustion

ABSTRACT: 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+ TILs away from exhausted effector states remains an elusive goal. Our work provides for the first-time evidence that orthogonal gene-engineering of T cells to secrete an IL-2-variant binding the IL-2R and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic 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 the novel opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE200535 | GEO | 2022/04/12

REPOSITORIES: GEO

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Orthogonal Gene Engineering Enables Novel Synthetic States of Powerful Tumor-rejecting CD8+ T Cells Escaping Canonical Exhaustion

Project description:Orthogonal Gene Engineering Enables Novel Synthetic States of Powerful Tumor-rejecting CD8+ T Cells Escaping Canonical Exhaustion

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