Targeting the Alternatively Spliced Soluble Isoform of CTLA-4: Prospects for Immunotherapy?

Ward, Frank J.; Dahal, Lekh N.; Khanolkar, Rahul C.; Shankar, Sucharita P.; Barker, Robert N.

doi:10.2217/imt.14.73

Cited by 22 publications

(21 citation statements)

References 98 publications

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“…Again, alternative RNA splicing can explain how more sBTLA is observed despite similar levels of gene expression. Alternative RNA splicing has been suggested as a mechanism for the production of other membrane bound immune checkpoint proteins such as PD-1 and CTLA-4 (Monaghan et al, 2016 ; Rossille et al, 2014 ; Ward et al, 2014 ). In the current study, the soluble form is created as a result of a premature stop codon from an alternative 3′ splice site (Fig.…”

Section: Discussionmentioning

confidence: 99%

Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness

Monaghan

Banerjee

Chung

et al. 2018

Mol Med

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BackgroundCritically ill patients with sepsis and acute respiratory distress syndrome have severely altered physiology and immune system modifications. RNA splicing is a basic molecular mechanism influenced by physiologic alterations. Immune checkpoint inhibitors, such as B and T Lymphocyte Attenuator (BTLA) have previously been shown to influence outcomes in critical illness. We hypothesize altered physiology in critical illness results in alternative RNA splicing of the immune checkpoint protein, BTLA, resulting in a soluble form with biologic and clinical significance.MethodsSamples were collected from critically ill humans and mice. Levels soluble BTLA (sBTLA) were measured. Ex vivo experiments assessing for cellular proliferation and cytokine production were done using splenocytes from critically ill mice cultured with sBTLA. Deep RNA sequencing was done to look for alternative splicing of BTLA. sBTLA levels were fitted to models to predict sepsis diagnosis.ResultssBTLA is increased in the blood of critically ill humans and mice and can predict a sepsis diagnosis on hospital day 0 in humans. Alternative RNA splicing results in a premature stop codon that results in the soluble form. sBTLA has a clinically relevant impact as splenocytes from mice with critical illness cultured with soluble BTLA have increased cellular proliferation.ConclusionsBTLA is produced as a result of alternative RNA splicing. This isoform of BTLA has biological significance through changes in cellular proliferation and can predict the diagnosis of sepsis.

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Section: Discussionmentioning

confidence: 99%

Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness

Monaghan

Banerjee

Chung

et al. 2018

Mol Med

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“…The upregulation of CTLA-4 by cAMP could be regulated at the transcriptional level or due to changes in the stability of CTLA-4 mRNA. Although the contribution of sCTLA-4 to immune regulation has been less studied, it has been reported to play a role as regulator of T cell responses and to potentiate Treg suppression functions ( 29 – 31 ). These findings are consistent with the enhanced suppression of cytokine production and T cell proliferation on both CD4 + and CD8 + T cell populations exerted by CD4 + CD25 + T lymphocytes pre-treated with CT.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Phenotype and Function of Human CD4+CD25+ T Regulatory Lymphocytes Mediated by cAMP-Elevating Agents

et al. 2016

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We have shown that cholera toxin (CT) and other cyclic AMP (cAMP)-elevating agents induce upregulation of the inhibitory molecule CTLA-4 in human resting CD4+ T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP-elevating agents on human CD4+CD25+ T cells, which include the T regulatory cells (Tregs) that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP-elevating agents induce upregulation of CTLA-4 in CD4+CD25− and further enhance its expression in CD4+CD25+ T cells. We observed an increase of two isoforms of mRNA coding for the membrane and the soluble CTLA-4 molecules, suggesting that the regulation of CTLA-4 expression by cAMP is at the transcriptional level. In addition, we found that the increase of cAMP in CD4+CD25+ T cells converts the CD4+CD25+Foxp3− T cells in CD4+CD25+Foxp3+ T cells, whereas the increase of cAMP in CD4+CD25− T cells did not upregulate Foxp3 in the absence of activation stimuli. To investigate the function of these cells, we performed an in vitro suppression assay by culturing CD4+CD25+ T cells untreated or pre-treated with CT with anti-CD3 mAbs-stimulated autologous peripheral blood mononuclear cell. We found that CT enhances the inhibitory function of CD4+CD25+ T cells, CD4+, and CD8+ T cell proliferation and IFNγ production are strongly inhibited by CD4+CD25+ T cells pre-treated with cAMP-elevating agents. Furthermore, we found that CD4+CD25+ T lymphocytes pre-treated with cAMP-elevating agents induce the upregulation of CD80 and CD86 co-stimulatory molecules on immature dendritic cells (DCs) in the absence of antigenic stimulation, however without leading to full DC maturation. These data show that the increase of intracellular cAMP modulates the phenotype and function of human CD4+CD25+ T cells.

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“…Soluble CTLA-4 is produced by Treg, but also resting T cells, monocytes, B cells and is capable of binding B7.1, B7.2 and B7-H2 (ICOS-L) on APC ( 106 ). This secretable isoform can also be produced by some non-immune cells such as pituitary cells ( 107 ).…”

Section: Modifying Current CI Therapiesmentioning

confidence: 99%

“…Indeed, selective antibody blockade of sCTLA-4 enhanced antigen-specific T cell responses in vitro significantly increasing cell proliferation and effector cytokine production compared with isotype or anti-CTLA-4 antibodies. Further, in the diffuse B16F10 murine model of metastatic melanoma, selective blockade had reduced the number of tumor lesions comparably with conventional anti-CTLA-4 antibody treatment ( 106 ).…”

Section: Modifying Current CI Therapiesmentioning

confidence: 99%

On the Road to Immunotherapy—Prospects for Treating Head and Neck Cancers With Checkpoint Inhibitor Antibodies

2018

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Head and neck cancers (HNC) represent a heterogeneous cluster of aggressive malignancies that account for 3% of all cancer cases in the UK. HNC is increasing in frequency particularly in the developing world, which is related to changes in risk factors. Unfortunately, the mortality rate is high, which is chiefly attributed to late diagnosis at stages where traditional treatments fail. Cancer immunotherapy has achieved great successes in anti-tumor therapy. Checkpoint inhibitor (CI) antibodies enhance anti-tumor activity by blocking inhibitory receptors to drive tumor-specific T and NK cell effector responses. Since their introduction in 2011, CI antibodies have been approved for many cancer types including HNC. Here, we examine the development of CI therapies and look forward to future developments for treatment of HNC with CI therapies.

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Targeting the Alternatively Spliced Soluble Isoform of CTLA-4: Prospects for Immunotherapy?

Cited by 22 publications

References 98 publications

Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness

Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness

Modulation of Phenotype and Function of Human CD4+CD25+ T Regulatory Lymphocytes Mediated by cAMP-Elevating Agents

On the Road to Immunotherapy—Prospects for Treating Head and Neck Cancers With Checkpoint Inhibitor Antibodies

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