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-2CD4 T cells had the gene signature of increased regulatory T cells (Treg); BCL-2CD8 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-2CD4 T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2CD4 T cells. BCL-2 expression in CD8T cells was associated with exhausted cells (PD-1Tim-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-2T 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.
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| http://dx.doi.org/10.1186/s12943-022-01516-w | DOI Listing |
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