Khanolkar, Rahul C, Zhang, Chu, Al-Fatyan, Farah, Lawson, Linda, Depasquale, Ivan, Meredith, Fiona M, Muller, Frank, Nicolson, Marianne, Dahal, Lekh Nath, Abu-Eid, Rasha et al (show 4 more authors)
(2022)
TGF beta 2 Induces the Soluble Isoform of CTLA-4-Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma.
FRONTIERS IN IMMUNOLOGY, 12.
763877-.
Abstract
Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on <i>in vitro</i> immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | checkpoint inhibitor, CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), melanoma, sCTLA-4, T cells, TGF beta 2 |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Jun 2022 09:51 |
| Last Modified: | 18 Jan 2023 21:00 |
| DOI: | 10.3389/fimmu.2021.763877 |
| Open Access URL: | https://doi.org/10.3389/fimmu.2021.763877 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3155990 |
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