Abstract
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.
Highlights
Despite the extensive research and the development of new treatment modalities, the number of chronic lymphocytic leukemia (CLL) cases with clinical resistance to therapy is constantly rising [1]
Starting from day 18th after TCL1 leukemia inoculation, we detected a significant decrease in the percentage of leukemic cells (CD5+CD19+), in the peripheral blood, of Diphtheria Toxin (DT)-treated mice as compared to untreated TCL1 leukemia-bearing animals (Figure 1B, left panel)
We observed the enrichment of effector (EFF; CD44+CD62L-) and central memory (CM; CD44+CD62L+) cells in both CD4+ and CD8+ T cell subpopulations in mice deprived of Tregs (Figures 1D, E)
Summary
Despite the extensive research and the development of new treatment modalities, the number of chronic lymphocytic leukemia (CLL) cases with clinical resistance to therapy is constantly rising [1]. The newest achievement in immunotherapy – chimeric antigen receptor T cells (CAR-T cells) – are less effective in CLL as compared to other B cell malignancies, including B cell acute lymphoblastic leukemia or diffuse large B cell lymphoma [2–4]. Antibodies against lymphocyte activation gene 3 (LAG-3), programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) are only effective when administrated in the initial stage of leukemia development [5–7]. The immune system dysfunctions observed in CLL patients, suggest that CLL cells modulate the microenvironment to their own benefit [8–10]. In order to improve the therapeutic strategies for CLL, it is crucial to understand the mechanisms that shape the leukemia microenvironment
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