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

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.