Abstract
BackgroundMechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. 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 scenarios.MethodsWe performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up).ResultsMolecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10.ConclusionsAltogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.
Highlights
Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood
Identification of patients that are at high risk of progression to advanced clinical stages needing treatment in chronic lymphocytic leukemia (CLL) is expedited by the use of different prognostic parameters including the mutational status of the IGHV genes or its surrogates like ZAP-70 expression [1, 2], chromosomal aberrations and gene mutations (i.e., TP53 or NOTCH1), [3, 4] or prognostic scores like the CLL-IPI [5]
Definition of progression and requirement for treatment were established following the international workshop on CLL (IWCLL) criteria [28]
Summary
Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. Identification of patients that are at high risk of progression to advanced clinical stages needing treatment in chronic lymphocytic leukemia (CLL) is expedited by the use of different prognostic parameters including the mutational status of the IGHV genes or its surrogates like ZAP-70 expression [1, 2], chromosomal aberrations and gene mutations (i.e., TP53 or NOTCH1), [3, 4] or prognostic scores like the CLL-IPI [5]. Changes in the gene expression profile of leukemic cells are infrequent at progression [16] These findings indicate that CLL progression from early stages is not mainly driven by genetic evolution, which highlights the potential role of the leukemic microenvironment in the evolution of the disease. The immunosuppressing microenvironment prevalent in CLL is boosted by the expansion of myeloid-derived suppressor cells (MDSCs) [23] and the production of IL-10 by CLL cells [24], among other factors
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