Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells
Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether
Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether
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Research Article Hematology Stem cells

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

Abstract

Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by CD8+ cytotoxic 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 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 regulators of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost antileukemic immunity in CML.

Authors

Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether

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Figure 3

Treg depletion reduces CML LSC numbers in vivo.

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Treg depletion reduces CML LSC numbers in vivo. (A) Experimental setup. ...
(A) Experimental setup. BCR-ABL1-GFP–transduced LSKs were injected i.v. into nonirradiated Foxp3DTR recipients. After establishment of the disease (day 13), mice were randomized to DT or PBS treatment (days 13, 14, 19, and 20; i.p.). (B) Kaplan-Meier survival curves of PBS- and DT-treated CML mice (PBS, n = 7; DT, n = 7); log-rank test. (C) Kaplan-Meier survival curve of secondary CML mice. BM cells of surviving primary CML mice were injected i.v. into lethally irradiated secondary BL/6 recipients, and survival was monitored (n = 6 surviving DT CML mice). (D–J) BM CD4+Foxp3-GFP+ Tregs (D), spleen weight (E), L-Gr-1+ cells (F), and absolute numbers of L-lin– cells (G), L–c-kithi (H), LSCs (I) in BM and colony formation capacity (J) per mouse was determined 21 days after CML induction (PBS: n = 7; DT: n = 8); t tests. (K) BM cells of primary CML mice (day 21) were injected i.v. into lethally irradiated secondary BL/6 recipients, and survival was monitored (PBS, n = 7; DT, n = 8); log-rank test. Data are displayed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Dotted lines represent the time point of the experiment termination at day 90.