In a recent publication in Cell Report Medicine (November 19, 2024), the authors explore a novel strategy to prevent T-cell exhaustion in the context of immuno-oncology. While adoptive cell therapies involving in vitro modified T cells can avoid immune exhaustion, the uncontrolled proliferation of these modified cells may lead to severe side effects, including potential neurotoxicity. Therefore, an alternative strategy of pharmacologically reprogramming patient T cells—allowing for controlled dosing and timing—could offer a safer therapeutic option. The paper’s main finding is that iberdomide, a therapeutic agent that induces degradation of IKAROS (IKZF1), can reprogram exhausted T cells, restoring them to an effector state.
Using CD3+ T cells from healthy donors, the authors developed several in vitro models to study T-cell exhaustion. They applied multi-omics approaches—including single-cell SHARE-seq and an arrayed CRISPR knockout screen combined with expression and proteomic analyses—to identify regulators of the exhaustion process. Among the candidates, IKAROS emerged as a key regulator, displaying a marked and consistent fold-change between effector and exhausted T cells. Crucially, a compound (iberdomide) that promotes IKAROS degradation is already in clinical testing.
To validate their hypothesis, the authors co-cultured T cells with the OE21 cancer cell line in the presence or absence of iberdomide. In the absence of iberdomide, T cells eventually lost their cytotoxic activity, resulting in the proliferation of OE21 cells. In contrast, treatment with iberdomide dramatically reduced the number of OE21 cells. Additionally, exhausted T cells exhibited epigenetic reprogramming back to an effector state.
Reference:
Criscione, S., Yu, Y., Liang, Y. et al. Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion.Cell Reports Medicine, Published November 19, 2024.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00551-2
Jieun Jeong (정지은), Ph.D. 