TGFb2 induces the soluble isoform of CTLA-4 – implications for CTLA-4 based checkpoint inhibitor antibodies in malignant melanoma

Rahul Chaitanya Khanolkar, Chu Zhang, Farah al-Fatyan, Linda G Lawson, Ivan Depasquale, Fiona Meredith, Frank Muller, Marianne Nicolson, Lekh Nath Dahal, Rasha Abu Eid, Sanjay Rajpara, Robert Norman Barker, Anthony Ormerod, Frank James Ward* (Corresponding Author)

*Corresponding author for this work

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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 in vitro 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.
Original languageEnglish
Article number763877
Number of pages14
JournalFrontiers in Immunology
Publication statusPublished - 5 Jan 2022


  • checkpoint inhibitor
  • CTLA-4 (cytotoxic T lymphocyte-associated antigen 4)
  • sCTLA-4
  • melanoma
  • TGFb2
  • T cells


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