Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity
Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity
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.
cancer, immune checkpoint, immune regulation, immunomodulation, immunotherapy, soluble CTLA-4
Kennedy, Paul T.
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Saulters, Emma L.
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Duckworth, Andrew D.
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Lim, Yeong Jer
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Woolley, John F.
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Slupsky, Joseph R.
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Cragg, Mark S.
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Ward, Frank J.
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Dahal, Lekh N.
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Kennedy, Paul T.
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Saulters, Emma L.
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Duckworth, Andrew D.
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Lim, Yeong Jer
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Woolley, John F.
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Slupsky, Joseph R.
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Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Ward, Frank J.
d1650707-a18e-45a3-adcb-04d444788530
Dahal, Lekh N.
be67afe7-766f-4115-8973-78ce5925aa44
Kennedy, Paul T., Saulters, Emma L., Duckworth, Andrew D., Lim, Yeong Jer, Woolley, John F., Slupsky, Joseph R., Cragg, Mark S., Ward, Frank J. and Dahal, Lekh N.
(2023)
Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity.
Molecular Therapy.
(doi:10.1016/j.ymthe.2023.11.028).
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.
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Accepted/In Press date: 30 November 2023
e-pub ahead of print date: 5 December 2023
Additional Information:
Funding Information:
Funding for this work was provided by a North West Cancer Research (NWCR), UK project grant. The authors would like to thank Southampton Antibody and Vaccine Group (Christine Penfold, Kerry Cox, and Martin Taylor) for the production and shipping of anti-sCTLA-4 antibody JMW-3B3. P.T.K. designed and conducted experiments and acquired, analyzed, and interpreted data. E.L.S. contributed to in vitro experiments. A.D.D. Y.J.L. J.F.W. and J.R.S. helped with mass cytometry data acquisition, analysis, and interpretation of data. F.J.W. and M.S.C. designed experiments, contributed critical reagents and cell lines, and interpreted data. P.T.K. J.R.S. and L.N.D. wrote the manuscript. L.N.D. acquired funding, designed the study, and analyzed and interpreted data. All authors read, edited, and approved the final manuscript. F.J.W. and L.N.D. are inventors on a patent (US8697845 B2) covering the use of the anti-sCTLA-4 monoclonal antibody as a therapeutic.
Funding Information:
Funding for this work was provided by a North West Cancer Research ( NWCR ), UK project grant. The authors would like to thank Southampton Antibody and Vaccine Group (Christine Penfold, Kerry Cox, and Martin Taylor) for the production and shipping of anti-sCTLA-4 antibody JMW-3B3.
Publisher Copyright:
© 2023 The Author(s)
Keywords:
cancer, immune checkpoint, immune regulation, immunomodulation, immunotherapy, soluble CTLA-4
Identifiers
Local EPrints ID: 485873
URI: http://eprints.soton.ac.uk/id/eprint/485873
ISSN: 1525-0016
PURE UUID: 1b2187a0-c1c8-4904-ab50-9e24f8d42377
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Date deposited: 03 Jan 2024 19:32
Last modified: 18 Mar 2024 02:47
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Contributors
Author:
Paul T. Kennedy
Author:
Emma L. Saulters
Author:
Andrew D. Duckworth
Author:
Yeong Jer Lim
Author:
John F. Woolley
Author:
Joseph R. Slupsky
Author:
Frank J. Ward
Author:
Lekh N. Dahal
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