BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion

Mol Cancer. 2022 Feb 22;21(1):59. doi: 10.1186/s12943-022-01516-w.


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.

Keywords: BCL-2; Chronic lymphocytic leukemia; Single-cell RNA sequencing; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / immunology
  • Humans
  • Immunosuppression Therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell* / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell* / metabolism
  • Proto-Oncogene Proteins c-bcl-2* / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2* / immunology
  • T-Lymphocytes, Cytotoxic* / immunology
  • T-Lymphocytes, Cytotoxic* / metabolism
  • Tumor Microenvironment


  • BCL2 protein, human
  • Proto-Oncogene Proteins c-bcl-2