Increased frequency of CD4⁺PD‐1⁺HLA‐DR⁺ T cells is associated with disease progression in CLL

Abstract

Summary Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T‐cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more phenotypically complex than those of healthy controls with significant increases in the frequencies of CD4 and CD8 memory T cells expressing exhaustion‐, activation‐ and senescence‐associated markers. Multivariate analysis of 111 different T‐cell subsets showed that high frequencies of four subsets (three CD8 and one CD4) were associated with shorter progression‐free survival. The most significant association was with CD4+HLA‐DR+PD‐1+ T cells, and patients could be stratified into high‐ and low‐risk groups based on the frequency of these T cells. The expansion of this CD4+ subset could not be accounted for by age, cytomegalovirus infection or increases in Treg cells. Overall, these results highlight two relatively simple biomarkers, percentage CD8+ and percentage CD4+PD‐1+HLA‐DR+ T cells, which can be used to risk‐stratify CLL patients, independent of other tumour‐associated markers. They also provide further evidence for the pivotal role of T cells in modulating the pathology of CLL.

Robust integration of single-cell cytometry datasets

“…Interestingly, we observed that the proportion of the T and NKT cell compartment was increased in CLL patients (Figure 2d), as were circulating stem cells (as identified by CD34+ expression), especially closer to treatment (Figure 2e), suggesting marrow stress with higher disease burden. In keeping with previously published data [14][15][16] , we saw a decrease in naive CD8+ T cells, with corresponding increase in the CD8+ TEMRA population when comparing close-to-treatment CLL samples to HDs (Supplementary Figure 3). The use of HLA-DR in the staining further identified groups of CD8+ and CD4+ effector memory T cells that increased between CLL time point 1 and 2 with the CD4+ cluster being specifically enriched for PD-1 (Figure 2f-g and Supplementary Figure 3), similar to that reported by Elston et al (2020) 15 .…”

Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

“…T H 2-polarized CD4 + T cells secrete cytokines that can limit CTL differentiation and proliferation such as IL-10 and IL-4, while CD4 + T Regs (FOXP3 + ) have significant immunosuppressive functions through various mechanisms and their pro-tumor role has been described in both solid tumors and lymphomas (13,(27)(28)(29). In CLL, in vitro and xenograft murine models have demonstrated a pro-tumor effect of the CD4 + T cell compartment in patients, with correlations of CD4 + subset counts and clinical outcome supporting this role (28,30). However, research using Eµ-TCL1-based murine models has suggested a more complex role of CD4 + T cells with some studies showing an anti-tumor function (31), while others demonstrating a dispensable role (23).…”

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…T cells from CLL patients have a higher expression of both the intracellular and surface forms of CTLA-4 compared to healthy controls (85,112). In addition, the upregulation of PD-1 was observed in CD4+ and CD8+ T cells from patients with CLL and was reported to associate with adverse prognosis (82,85,89,113). PD-1 expression is further increased in T cells from the lymphnode compared to the peripheral blood compartment (90,114).…”