A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia

Frontiers in Immunology

Federica Benvenuti¹  Francesca Simoncello¹  Przemyslaw Juszczynski²  Joanna Barankiewicz²  Aleksander Salomon-Perzynski²  Ewa Lech-Maranda²  Patrycja Nowakowska³  Angelika Muchowicz³  Malgorzata Firczuk³  Agnieszka Goral³  Marta Sledz³  Karolina Siudakowska³  Klaudyna Fidyt³  Stefania Gobessi⁴  Dimitar G. Efremov⁴  Etienne Moussay⁵  Jérôme Paggetti⁵  Giulia Pagano⁵ 

[1] Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy;Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;Department of Immunology, Medical University of Warsaw, Warsaw, Poland;Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy;Tumor-Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg;

关键词: Tregs;    CLL;    Eµ-TCL1;    MALT1;    TCR repertoire;    anti-leukemic immune response;   

DOI  :  10.3389/fimmu.2022.781364

来源: DOAJ

【 摘 要 】

Regulatory T cells (Tregs) are capable of inhibiting the proliferation, activation and function of T cells and play an important role in impeding the immune response to cancer. In chronic lymphocytic leukemia (CLL) a dysfunctional immune response and elevated percentage of effector-like phenotype Tregs have been described. In this study, using the Eµ-TCL1 mouse model of CLL, we evaluated the changes in the Tregs phenotype and their expansion at different stages of leukemia progression. Importantly, we show that Tregs depletion in DEREG mice triggered the expansion of new anti-leukemic cytotoxic T cell clones leading to leukemia eradication. In TCL1 leukemia-bearing mice we identified and characterized a specific Tregs subpopulation, the phenotype of which suggests its role in the formation of an immunosuppressive microenvironment, supportive for leukemia survival and proliferation. This observation was also confirmed by the gene expression profile analysis of these TCL1-specific Tregs. The obtained data on Tregs are consistent with those described so far, however, above all show that the changes in the Tregs phenotype described in CLL result from the formation of a specific, described in this study Tregs subpopulation. In addition, functional tests revealed the ability of Tregs to inhibit T cells that recognize model antigens expressed by leukemic cells. Moreover, inhibition of Tregs with a MALT1 inhibitor provided a therapeutic benefit, both as monotherapy and also when combined with an immune checkpoint inhibitor. Altogether, activation of Tregs appears to be crucial for CLL progression.

【 授权许可】

Unknown