Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity.

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.

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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⁺ 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⁺ T cells in a non-cytotoxic state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoral CD8⁺ 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
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:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3177567