Molecular cancer · 2022
BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion.
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Liu Lu, Cheng Xianfeng, Yang Hui, Lian Senlin, Jiang Yuegen, Liang Jinhua, Chen Xiao, Mo Suo, Shi Yu, Zhao Sishu, Li Jianyong, Jiang Runqiu, Yang Dong-Hua, Wu Yujie
Аннотация
BACKGROUND: Chronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment.
METHODS: The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored.
RESULTS: We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2-CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell-associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax.
CONCLUSION: BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.
METHODS: The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored.
RESULTS: We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2-CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell-associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax.
CONCLUSION: BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.