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

Paul T Kennedy; Emma L Saulters; Andrew D Duckworth; Yeong Jer Lim; John F Woolley; Joseph R Slupsky; Mark S Cragg; Frank J Ward; Lekh N Dahal

doi:10.1016/j.ymthe.2023.11.028

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

Paul T Kennedy, Emma L Saulters, Andrew D Duckworth, Yeong Jer Lim, John F Woolley, Joseph R Slupsky, Mark S Cragg, Frank J Ward, Lekh N Dahal

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Journal	Molecular Therapy
Early online date	5 Dec 2023
DOIs	https://doi.org/10.1016/j.ymthe.2023.11.028
Publication status	E-pub ahead of print - 5 Dec 2023

Bibliographical note

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.

Data Availability Statement

All data generated are presented in the figures and supplemental information. Materials are available upon reasonable request.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ymthe.2023.11.028Licence: CC BY

Cite this

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title = "Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity",

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. ",

author = "Kennedy, {Paul T} and Saulters, {Emma L} and Duckworth, {Andrew D} and Lim, {Yeong Jer} and Woolley, {John F} and Slupsky, {Joseph R} and Cragg, {Mark S} and Ward, {Frank J} and Dahal, {Lekh N}",

note = "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.",

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AU - Kennedy, Paul T

AU - Saulters, Emma L

AU - Duckworth, Andrew D

AU - Lim, Yeong Jer

AU - Woolley, John F

AU - Slupsky, Joseph R

AU - Cragg, Mark S

AU - Ward, Frank J

AU - Dahal, Lekh N

N1 - 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.

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N2 - 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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