Long-term persistence and functionality of adoptively transferred antigen-specific T cells with genetically ablated PD-1 expression

Dötsch S, Svec M, Schober K, Hammel M, Wanisch A, Gökmen F, Jarosch S, Warmuth L, Barton J, Cicin-Sain L, D'Ippolito E, Busch DH (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 120

Pages Range: e2200626120

Journal Issue: 10

DOI: 10.1073/pnas.2200626120

Abstract

Engagement of the inhibitory T cell receptor programmed cell death protein 1 (PD-1) associates with dysfunctional states of pathogen- or tumor-specific T cells. Accordingly, systemic antibody-mediated blockade of PD-1 has become a central target for immunotherapies but is also associated with severe toxicities due to loss of peripheral tolerance. Therefore, selective ablation of PD-1 expression on adoptively transferred T cells through direct genetic knockout (KO) is currently being explored as an alternative therapeutic approach. However, since PD-1 might also be required for the regulation of physiological T cell function and differentiation, the suitability of PD-1 as an engineering target is controversial. In this study, we systematically investigated the maintenance of T cell functionality after CRISPR/Cas9-mediated PD-1 KO in vivo during and after acute and chronic antigen encounter. Under all tested conditions, PD-1 ablation preserved the persistence, differentiation, and memory formation of adoptively transferred receptor transgenic T cells. Functional PD-1 KO T cells expressing chimeric antigen receptors (CARs) targeting CD19 could be robustly detected for over 390 d in a syngeneic immunocompetent mouse model, in which constant antigen exposure was provided by continuous B cell renewal, representing the longest in vivo follow-up of CAR-T cells described to date. PD-1 KO CAR-T cells showed no evidence for malignant transformation during the entire observation period. Our data demonstrate that genetic ablation of PD-1 does not impair functionality and longevity of adoptively transferred T cells per se and therefore may be pursued more generally in engineered T cell-based immunotherapy to overcome a central immunosuppressive axis.

Authors with CRIS profile

Kilian Schober

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE)

How to cite

APA:

Dötsch, S., Svec, M., Schober, K., Hammel, M., Wanisch, A., Gökmen, F.,... Busch, D.H. (2023). Long-term persistence and functionality of adoptively transferred antigen-specific T cells with genetically ablated PD-1 expression. Proceedings of the National Academy of Sciences of the United States of America, 120(10), e2200626120. https://dx.doi.org/10.1073/pnas.2200626120

MLA:

Dötsch, Sarah, et al. "Long-term persistence and functionality of adoptively transferred antigen-specific T cells with genetically ablated PD-1 expression." Proceedings of the National Academy of Sciences of the United States of America 120.10 (2023): e2200626120.

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