Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T‐cells in chronic lymphocytic leukemia

Abstract

Antitumor immunity in chronic lymphocytic leukemia (CLL) is hampered by highly dysfunctional T-cells. Although certain T-cell subsets have been reported to be of prognostic significance in this disease, their interplay is complex and it remains incompletely understood which of these subsets significantly drive CLL progression. Here, we determined immunological profiles of 24 circulating T-cell subsets from 79 untreated individuals by multiparametric flow cytometry. This screening cohort included healthy donors, patients with monoclonal B-cell lymphocytosis (MBL), Rai 0 CLL and advanced CLL. We applied multidimensional scaling analysis as rigorous and unbiased statistical tool to globally assess the composition of the circulating T-cell environment and to generate T-cell scores reflecting its integrity. These scores allowed clear distinction between advanced CLL and healthy controls, whereas both MBL and Rai 0 CLL showed intermediate scores mirroring the biological continuum of CLL and its precursor stages. T-cell stimulation and suppression assays as well as longitudinal T-cell profiling showed an increasingly suppressive regulatory function initiating at the MBL stage. Effector function was impaired only after transition to CLL and partially recovered after chemoimmunotherapy. In an independent validation cohort of 52 untreated CLL cases, aberrant T-cell profiles were significantly associated with shorter time to treatment independently of other prognostic parameters. Random forest modeling predicted regulatory T-cell, gamma/delta and NKT-cells, as well as exhaustion of the CD81 subset as potential drivers of progression. Our data illustrate a pathological T-cell environment in MBL that evolves toward a more and more suppressive and prognostically relevant profile across the disease stages.

The expression of CD39 on regulatory T cells is genetically driven and further upregulated at sites of inflammation

“…Moreover, CD39 þ Tregs are overrepresented in patients with cancer and AIDS [17,32], conditions that require less regulatory activity for healing. Thus, modulating the activity of this The region comprising rs10748643 nucleotide polymorphism (SNP) in the ENTPD1 gene was sequenced and the donors were grouped according to their genotype: A/A, A/G and G/G (n ¼ 5, 7 and 6 donors, respectively).…”

Mechanisms of PD-L1/PD-1–mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model

“…4,7,18 Previous studies in Em-TCL1 mice demonstrated that molecular T-cell defects and subset changes can be modeled in leukemic mice, 28,29,32 but have failed to take full advantage of the availability of different microenvironments. In CLL patients, T-cell defects and associations with aggressive disease/poor outcome have been extensively characterized, 3,4,6,18,[33][34][35][36][37] but have focused largely on PB. However, different organs provide distinct and unique microenvironments for CLL cells, 20,21 and it is not known if the same holds true for T cells.…”

T-cell diversification reflects antigen selection in the blood of patients on immune checkpoint inhibition and may be exploited as liquid biopsy biomarker

“…Measurements were performed on a Navios flow cytometer (Beckman Coulter, Krefeld, Germany). The gating strategy has been previously described including raw data sets for this flow cytometry immunoprofiling approach …”