4-1BBL–containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells

Blood Advances - Tập 6 - Trang 1879-1894 - 2022
Julian Swatler1, Laura Turos-Korgul1, Marta Brewinska-Olchowik1, Sara De Biasi2, Wioleta Dudka1,3, Bac Viet Le1,4, Agata Kominek1, Salwador Cyranowski5,6, Paulina Pilanc5, Elyas Mohammadi7, Dominik Cysewski8, Ewa Kozlowska9, Wioleta Grabowska-Pyrzewicz10, Urszula Wojda10, Grzegorz Basak11, Jakub Mieczkowski7, Tomasz Skorski4, Andrea Cossarizza2,12, Katarzyna Piwocka1
1Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland
2Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
3Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
4Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
5Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
6Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
7P-Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland
8Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Warsaw, Poland
9Department of Immunology, Faculty of Biology, University of Warsaw, Warsaw, Poland
10Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Warsaw, Poland
11Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
12National Institute for Cardiovascular Research, Bologna, Italy

Tóm tắt

AbstractChronic and acute myeloid leukemia evade immune system surveillance and induce immunosuppression by expanding proleukemic Foxp3+ regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse, and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias remain largely unexplored. Here, we identify leukemic extracellular vesicles (EVs) as drivers of effector proleukemic Tregs. Using mouse model of leukemia-like disease, we found that Rab27a-dependent secretion of leukemic EVs promoted leukemia engraftment, which was associated with higher abundance of activated, immunosuppressive Tregs. Leukemic EVs attenuated mTOR-S6 and activated STAT5 signaling, as well as evoked significant transcriptomic changes in Tregs. We further identified specific effector signature of Tregs promoted by leukemic EVs. Leukemic EVs-driven Tregs were characterized by elevated expression of effector/tumor Treg markers CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, and IL21R and included 2 distinct effector Treg (eTreg) subsets: CD30+CCR8hiTNFR2hi eTreg1 and CD39+TIGIThi eTreg2. Finally, we showed that costimulatory ligand 4-1BBL/CD137L, shuttled by leukemic EVs, promoted suppressive activity and effector phenotype of Tregs by regulating expression of receptors such as CD30 and TNFR2. Collectively, our work highlights the role of leukemic extracellular vesicles in stimulation of immunosuppressive Tregs and leukemia growth. We postulate that targeting of Rab27a-dependent secretion of leukemic EVs may be a viable therapeutic approach in myeloid neoplasms.

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Blood Advances

Tập 6

1879-1894

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