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| Home > Articles > Published articles > Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia |
(Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Pompeu Fabra) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Universitat Autònoma de Barcelona. Departament de Medicina) (Universitat Autònoma de Barcelona. Departament de Medicina) (Vall d'Hebron Institut d'Oncologia)
| Date: | 2021 |
| Abstract: | Mechanisms 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. We 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). Molecular 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-bet dim/− Eomes hi PD1 hi) 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. Altogether, 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. The online version contains supplementary material available at 10. 1186/s40364-021-00290-z. |
| Grants: | Instituto de Salud Carlos III III/PI17/00950 Instituto de Salud Carlos III III/PI18/01392 Instituto de Salud Carlos III III/PI17/00943 Instituto de Salud Carlos III III/PT17/0009/0019 Ministerio de Ciencia e Innovación PTQ-16-08623 Ministerio de Ciencia e Innovación RYC-2012-2018 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | CLL ; Immune evasion ; Clinical progression ; T cell exhaustion |
| Published in: | Biomarker Research, Vol. 9 (may 2021) , ISSN 2050-7771 |
