TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity
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Abstract
Clinical TCR gene therapy of melanoma represents a feasible and promising treatment
rationale yet is currently challenged by objective response rates that stay behind
those observed with conventional adoptive T cell therapy. Here, the phenotype and
function of TCR-transduced T cells, considered to determine the efficacy of TCR gene
therapy, were studied in relation to T cell activation and cytokine treatments. We
observed that the lectin Concanavalin A (ConA), and to a lesser extent anti-CD3 and
CD28 mAbs (soluble CD3/CD28), resulted in functional surface expression of the TCRalphabeta
transgenes and enhanced fractions of CD62L(hi), CD44(lo) naive T cells. T cell functions
and limited T cell differentiation were most significant when T cells were treated
with a combination of IL-15 and IL-21 rather than IL-2. In comparison, anti-CD3 and
CD28 mAbs coated to either latex or polystyrene beads (polystyrene or latex CD3/CD28)
resulted in improved TCR expression levels and enhanced T cell differentiation irrespective
of cytokine treatment, with effects most pronounced for polystyrene CD3/CD28. T cells
demonstrated enhanced cytotoxic activity and IFNgamma production when activated with
CD3/CD28 beads and treated with IL-15 and IL-21, but at the same time displayed non-specific
T cell responses. In contrast, ConA and soluble CD3/CD28 activations resulted in antigen-specific
T cell responses. In short, we show that retroviral TCR engineering of primary T cells
benefits from activation with ConA or soluble CD3/CD28 rather than immobilized anti-CD3
and CD28 mAbs with respect to T cell differentiation and antigen-specificity of T
cell responses.
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