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. 2021 Jun 14;10(1):1938475.
doi: 10.1080/2162402X.2021.1938475.

Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults

Aditya Arra  1   2 , Maximilian Pech  1   2 , Hang Fu  1   2 , Holger Lingel  1   2 , Franziska Braun  1   2 , Christian Beyer  3 , Myra Spiliopoulou  3 , Barbara M Bröker  4 , Karen Lampe  5 , Christoph Arens  2   5 , Katrin Vogel  1   2 , Mandy Pierau  1   2 , Monika C Brunner-Weinzierl  1   2
Affiliations

Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults

Aditya Arra et al. Oncoimmunology. .

Abstract

The monoclonal antibody against CTLA-4, Ipilimumab, is a first-in-class immune-checkpoint inhibitor approved for treatment of advanced melanoma in adults but not extensively studied in children. In light of the fact that the immune response early in life differs from that of adults, we have applied a human in vitro model stimulating CD4+ T-cells from neonates, children (1-5 years), and adults antigen-specifically with Staphylococcus aureus (S. aureus) for assessment of CTLA-4 blockade early in life. We show that T-cell proliferation as well as frequencies of antigen-specific T-cells (CD40L+CD4+) were enhanced in neonatal T-cells upon CTLA-4 blockade showing a larger variance within the group (F-test p < .0001). Using machine learning algorithm Random Forest, adult and neonatal T-cell responses can be unambiguously categorized (F1 score-0.75) on the basis of their cytokine (co-)expression. Blockade of CTLA-4 enhanced frequencies of IL-8, IFNγ, and IL-10 producers among CD40L+ T-cells. Of note, antigen-specific T-cells from neonates displayed higher cytokine coproduction at baseline, while T-cells from children caught up to neonates, and adults to baseline of children upon CTLA-4 blockade. These findings reveal that in neonatal T-cells blockade of CTLA-4 mainly unleashes the antigen-specific capacity by increasing the numbers of responding T-cells, whereas in children and adults it promotes the coexpression of cytokines by individual T-cells. Thus, CTLA-4 blockade boosts antitumor immunity through different mechanisms depending on the patients' age. These data implicate a strong impact of the developmental stage of the T-cell compartment on the effects of immune-checkpoint therapy.

Keywords: CD40L; CTLA-4; S. aureus; adults; children; multifunctional T-cells; neonates.

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Conflict of interest statement

The authors declare no financial or commercial conflict of interest.

Figures

Figure 1.
Figure 1.
Antigen-specific T-cell responses of different age groups
Figure 2.
Figure 2.
Impact of CTLA-4 blockade on antigen-specific CD4+ T-cell responsiveness of adults, children and neonates
Figure 3.
Figure 3.
Cytokine expression in antigen-specific T helper cells from neonates, children, and adults after blockade of CTLA-4
Figure 4.
Figure 4.
Age-dependent diversity of CTLA-4 blockade in regulating high-quality cytokine coproducers
See this image and copyright information in PMC

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