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Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5high and CD5low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5high and CD5low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n = 60) subgrouped according to the IgHV mutational status (IgHVmut, n = 24; IgHVunmut, n = 36). CD5high subpopulation showed a high percentage of CXCR3 (P < 0.001), CCR10 (P = 0.001), and CD62L (P = 0.031) and high levels of CXCR5 (P = 0.005), CCR7 (P = 0.013) compared to CD5low cells expressing high CXCR4 (P < 0.001). Comparing IgHVmut and IgHVunmut patients, high levels of CXCR3 on CD5high and CD5low subpopulations were detected in the IgHVmut patients, with better discrimination in CD5low subpopulation. Levels of CXCR3 on CD5low subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5high and CD5low neoplastic cells in IgHVmut with a better prognosis compared to IgHVunmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations. [ABSTRACT FROM AUTHOR]

Highlights • Ibrutinib influences the expression of HLA-DR on CLL cells. • Ibrutinib gradually increases HLA-DR levels on circulating monocyte subsets. • Immunomodulatory effect of ibrutinib on CLL, T cells, monocytes is time-dependent. Abstract There is the first evidence of changes in the kinetics of B cell antigen receptor (BCR) internalisation of neoplastic cells in chronic lymphocytic leukemia (CLL) after the short-term and long-term administration of ibrutinib. We aimed to assess the influence of short-term and long-term ibrutinib treatment on the HLA-DR expression on CLL cells, T cells and monocytes. The immunophenotyping of CLL and immune cells in peripheral blood was performed on 16 high-risk CLL patients treated with ibrutinib. After early ibrutinib administration, the HLA-DR expression on CLL cells reduced ( P = 0.032), accompanied by an increase in CLL cell counts in peripheral blood ( P = 0.001). In vitro culturing of CLL cells with ibrutinib also revealed the reduction in the HLA-DR expression at protein and mRNA levels ( P < 0.01). The decrease in HLA-DR on CLL cells after the first month was followed by the gradual increase of its expression by the 12th month ( P = 0.001). A one-month follow-up resulted in elevated absolute counts of CD4+ ( P = 0.002) and CD8+ ( P < 0.001) T cells as well as CD4+ and CD8+ cells bearing HLA-DR ( P < 0.01). The long-term administration of ibrutinib was associated with the increased numbers of CD4+ bearing HLA-DR ( P = 0.006) and elevation of HLA-DR expression on all monocyte subsets ( P ≤ 0.004). Our results provide the first evidence of the time-dependent immunomodulatory effect of ibrutinib on CLL and T cells and monocytes. The clinical consequences of time-dependent changes in HLA-DR expression in ibrutinib treated patients deserve further investigation. [ABSTRACT FROM AUTHOR]

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5 high and CD5 low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5 high and CD5 low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients ( n = 60) subgrouped according to the IgHV mutational status ( IgHV mut , n = 24; IgHV unmut , n = 36). CD5 high subpopulation showed a high percentage of CXCR3 ( P < 0.001), CCR10 ( P = 0.001), and CD62L ( P = 0.031) and high levels of CXCR5 ( P = 0.005), CCR7 ( P = 0.013) compared to CD5 low cells expressing high CXCR4 ( P < 0.001). Comparing IgHV mut and IgHV unmut patients, high levels of CXCR3 on CD5 high and CD5 low subpopulations were detected in the IgHV mut patients, with better discrimination in CD5 low subpopulation. Levels of CXCR3 on CD5 low subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5 high and CD5 low neoplastic cells in IgHV mut with a better prognosis compared to IgHV unmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Gayane Manukyan et al.)