Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells.

Hinterbrandner, Magdalena; Rubino, Viviana; Stoll, Carina; Forster, Stefan; Schnüriger, Noah Samuel; Radpour, Ramin; Bärlocher, Gabriela M.; Ochsenbein, Adrian F.; Riether, Carsten (2021). Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells. JCI insight, 6(23) JCI Insight 10.1172/jci.insight.151797

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Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by cytotoxic CD8+ T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML bone marrow (BM), protected LSCs from MHC-class I dependent CD8+ CTL-mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4-signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL-mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulator of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost anti-leukemic immunity in CML.

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