TY - JOUR
T1 - 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
AU - Goral, Agnieszka
AU - Firczuk, Malgorzata
AU - Fidyt, Klaudyna
AU - Sledz, Marta
AU - Simoncello, Francesca
AU - Siudakowska, Karolina
AU - Pagano, Giulia
AU - Moussay, Etienne
AU - Paggetti, Jérôme
AU - Nowakowska, Patrycja
AU - Gobessi, Stefania
AU - Barankiewicz, Joanna
AU - Salomon-Perzynski, Aleksander
AU - Benvenuti, Federica
AU - Efremov, Dimitar G.
AU - Juszczynski, Przemyslaw
AU - Lech-Maranda, Ewa
AU - Muchowicz, Angelika
N1 - Funding information: This work was supported by: the Polish National Science Centre grants 2018/29/B/NZ6/01962 (AM) and 2016/21/B/NZ7/02041 (MF) and the Ministry of Science and Higher Education within “Regional Initiative of Excellence” program in the years 2019-2022 - 013/RID/2018/19, the FNRS “Télévie” 7.6518.20 (GP), and the Fonds National de la Recherche Luxembourg TIME-CLL: C20/BM/14582635 (EM).
PY - 2022/2/28
Y1 - 2022/2/28
N2 - 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.
AB - 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.
KW - anti-leukemic immune response
KW - CLL
KW - Eµ-TCL1
KW - MALT1
KW - TCR repertoire
KW - Tregs
UR - http://www.scopus.com/inward/record.url?scp=85126727017&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35296093
U2 - 10.3389/fimmu.2022.781364
DO - 10.3389/fimmu.2022.781364
M3 - Article
C2 - 35296093
AN - SCOPUS:85126727017
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 781364
ER -