Kennedy, Paul T ORCID: 0000-0001-5668-9132, Saulters, Emma L ORCID: 0009-0000-0273-0873, Duckworth, Andrew D, Lim, Yeong Jer, Woolley, John F, Slupsky, Joseph R ORCID: 0000-0002-7410-9004, Cragg, Mark S ORCID: 0000-0003-2077-089X, Ward, Frank J and Dahal, Lekh N ORCID: 0000-0001-8390-6593
(2024)
Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity.
Molecular therapy : the journal of the American Society of Gene Therapy, 32 (2).
pp. 457-468.
Abstract
CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumor control. Antibodies targeting CTLA-4 have been promising treatments for numerous cancers, but the mechanistic basis of their anti-tumoral immune-boosting effects is poorly understood. Although the ctla4 gene also encodes an alternatively spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in a murine cancer model. We show that expression of sCTLA-4 by tumor cells suppresses CD8<sup>+</sup> T cells in vitro and accelerates growth and experimental metastasis of murine tumors in vivo. These effects were accompanied by modification of the immune infiltrate, notably restraining CD8<sup>+</sup> T cells in a non-cytotoxic state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoral CD8<sup>+</sup> T cell activation and cytolytic potential, correlating with therapeutic efficacy and tumor control. This previously unappreciated role of sCTLA-4 suggests that the biology and function of multi-gene products of immune checkpoint receptors need to be fully elucidated for improved mechanistic understanding of cancer immunotherapies.
Item Type: | Article |
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Uncontrolled Keywords: | CD8-Positive T-Lymphocytes, Animals, Mice, Neoplasms, Protein Isoforms, Antibodies, CTLA-4 Antigen |
Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology > School of Life Sciences |
Depositing User: | Symplectic Admin |
Date Deposited: | 20 Dec 2023 14:19 |
Last Modified: | 16 Feb 2024 12:57 |
DOI: | 10.1016/j.ymthe.2023.11.028 |
Open Access URL: | https://doi.org/10.1016/j.ymthe.2023.11.028 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177567 |