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CD8+ T-cell exhaustion induced by leukemic cells drives progression in Chronic Lymphocytic Leukemia

ABSTRACT: Mechanisms mediating to disease progression from diagnosis in chronic lymphocytic leukemia (CLL) are not fully elucidated. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological landscapes. For that, we analyzed paired samples obtained from CLL patients at diagnosis and progression before front-line treatment or at diagnosis and long-term asymptomatic follow-up. By whole-exome sequencing, we found that CLL cells displayed limited genetic evolution at progression. Conversely, T cells from progressing patients showed significant immunophenotypical and transcriptional changes over time not observed in patients that did not progress. Specifically, we found that CD8+ T cells at progression were characterized by an increasing terminally exhausted effector phenotype (T-betdim/-EomeshiPD1hi) with high co-expression of inhibitory receptors (PD1, CD244 and CD160). This exhausted status in CD8+ T cells was induced by progressing leukemic cells mainly through a mechanism dependent on soluble factors, including IL-10. Thus, we demonstrate that immunological changes are of paramount importance for CLL clinical progression, thereby providing a rationale for the use of early immunotherapeutic intervention in this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141787 | GEO | 2021/01/09

REPOSITORIES: GEO

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CD8+ T-cell exhaustion induced by leukemic cells drives progression in Chronic Lymphocytic Leukemia

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