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

Bibliographical note

This work was funded by the Chief Scientist’s office, Scotland grant no. ETM/280.
Microscopy was performed in the Microscopy and Histology Core Facility at the University of Aberdeen. Flow cytometry was performed in the Iain Fraser Cytometry Centre. We are very grateful to our lab manager Ms. Gill Moir for her assistance with this work and also to the many BSc/MSc project students who worked on this project. We are extremely grateful for all of the volunteer melanoma patient donors and healthy donors that supported this work. FA-F received an Elphinstone PhD scholarship funded by the School of Medicine, Medical Sciences & Nutrition at the University of Aberdeen.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
The Supplementary Material for this article can be found online at:


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


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