TCRs equipped with ICOS signaling domain enhance number of intra-tumoral T cells and mediate complete anti-tumor responses

Identification: 2025


Description

TCRs equipped with ICOS signaling domain enhance number of intra-tumoral T cells and mediate complete anti-tumor responses

Kunert A1, Berrevoets C1, Wijers R1, Bouzid R, Peters M1, Abken H2, Debets R1

1Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 2Department I of Internal Medicine; University Hospital Cologne and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

Adoptive therapy with TCR-engineered T cells constitutes an effective treatment approach for patients with malignant disease, but is currently challenged by incomplete responses. Lack of intra-tumoral co-stimulation may contribute to immune evasion of tumors, and consequently lead to short-term responses and recurrences of tumors, a process often accompanied by low numbers and reduced activity of tumor-infiltrating T cells (Straetemans T, Mol Ther, 2015).

Here we tested the therapeutic value of TCRs that are equipped with the intracellular domain of either the co-stimulatory receptors CD28, CD40L, OX40 or ICOS, preceded by the transmembrane domain of CD28 (in extension to earlier work: Govers C, J Immunol, 2014). These co-stimulatory TCRs were gene transfered into murine T cells and subsequently tested for their impact on in vitro and in vivo T cell function in comparison to wt TCR. These new TCRs demonstrated enhanced cell surface expression and pMHC binding, except for TCR:CD40L which showed only negligible expression. Remarkably, functional T cell avidity was generally decreased compared to wt TCR, a finding which did not limit the in vivo potential of these TCRs. In fact, adoptive transfer of T cells equipped with co-stimulatory TCRs into immune competent, melanoma-bearing mice (tumor sizes > 400mm3) resulted in prolonged anti-tumor responses and survival. Notably, almost all mice treated with TCR:ICOS T cells became tumor-free and more than 50% of the mice were still cured at the end of experiment (day 80 following start of therapy; compared to about 15% cure in other TCR groups). We observed that numbers of TCR, CD4-positive T cells in blood significantly correlated to delayed tumor recurrence, and that TCR:ICOS in particular resulted in high numbers of intra-tumoral T cells, and decreased expression of co-inhibitory receptors on these T cells.

In conclusion, T cells equipped with ICOS-containing TCRs significantly improved long-term clearance of tumors, arguing for further translational studies into the therapeutic potential of this TCR.

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