Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell–Derived IFN-γ by a T-bet–Dependent Mechanism

Abstract

Chronic lymphocytic leukemia (CLL) is a B cell malignancy associated with increased levels of inflammatory cytokines. Similarly, expression of CD38 on CLL cells correlates with CLL cell survival and proliferation, but the mechanisms that regulate CD38 expression and inflammatory cytokines remain unclear. We have recently demonstrated that patients have CLL-specific Th cells that support CLL proliferation. In this article, we show that CLL cells attract such Th cells, thereby establishing an Ag-dependent collaboration. Blocking experiments performed in vitro as wells as in vivo, using a xenograft model, revealed that secretion of IFN-γ was a major mechanism by which CLL-specific Th cells increased CD38 on CLL cells. The expression of the transcription factor T-bet in peripheral blood CLL cells significantly correlated with CD38 expression, and transient transfection of CLL cells with T-bet resulted in T-bethiCD38hi cells. Finally, chromatin immunoprecipitation experiments revealed that T-bet can bind to regulatory regions of the CD38 gene. These data suggest that CLL cells attract CLL-specific Th cells and initiate a positive feedback loop with upregulation of T-bet, CD38, and type 1 chemokines allowing further recruitment of Th cells and increased type 1 cytokine secretion. This insight provides a cellular and molecular mechanism that links the inflammatory signature observed in CLL pathogenesis with CD38 expression and aggressive disease and suggests that targeting the IFN-γ/IFN-γR/JAK/STAT/T-bet/CD38 pathway could play a role in the therapy of CLL.

Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient process

“…21) and the finding that only with T cells can normal B cells developing from xenografts of healthy human CD34 + cells acquire a mature phenotype and become Ig-secreting cells (48) support this possibility. Our studies, however, do not indicate T cell cognate recognition and interactions as mechanisms for B cell maturation, as suggested by others (49), and a cytokine-mediated (e.g., IFNγ) process is possible. In this regard, passage of normal naive T cells into alymphoid mice can lead to 2 T cell subsets: a slowly proliferating population and a rapidly dividing one that quickly develops a memory phenotype and secretes IFNγ (50), as in our findings (Figure 7, C and D).…”

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL)

“…On the other hand, it is tempting to speculate that some of the beneficial clinical activity of idelalisib in CLL may be related to breaking T reg -cell-mediated immune tolerance to the CLL cells, as recently described in mouse models of solid tumors (Ali et al 2014). In addition, there is evidence that Th1 cells can support CLL activation and proliferation (Burgler et al 2015; Os et al 2013) and PI3Kδ inhibition can suppress Th1 responses (Okkenhaug et al 2006; Soond et al 2010). None of these issues have yet been experimentally addressed in the context of CLL, and therefore, studies of the effects of idelalisib on T cell subsets in CLL patients should become an important part of future correlative studies.…”

Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia

“…The functional role of these clonally expanded T cells in CLL patients remains controversial; both pro-tumoral and tumor-suppressive activities have been discussed (32–35). In addition to CLL-promoting CD4 + cells (32, 33), other studies characterized cytotoxic T lymphocytes (CTLs) that recognize CLL specific idiotype peptides or other tumor-associated antigens (34, 35) and identified leukemia-associated mono/oligoclonal T cells within the circulating T cell compartment (7). However, these tumor-associated-antigen specific T cell clones apparently cannot effectively eliminate the malignant B cells, which may be related to T cell exhaustion.…”