Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

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  • dc.contributor.author Jiménez, Isabel
  • dc.contributor.author Tazón-Vega, Bárbara
  • dc.contributor.author Abrisqueta, Pau
  • dc.contributor.author Nieto, Juan C.
  • dc.contributor.author Bobillo, Sabela
  • dc.contributor.author Palacio-García, Carles
  • dc.contributor.author Carabia, Júlia
  • dc.contributor.author Valdés-Mas, Rafael
  • dc.contributor.author Munuera, Magdalena
  • dc.contributor.author Puigdefàbregas, Lluís
  • dc.contributor.author Parra Farré, Genís
  • dc.contributor.author Esteve-Codina, Anna
  • dc.contributor.author Franco-Jarava, Clara
  • dc.contributor.author Iacoboni, Gloria
  • dc.contributor.author Terol, María-José
  • dc.contributor.author García-Marco, J. A.
  • dc.contributor.author Crespo Barrio, Marta
  • dc.contributor.author Bosch, Francesc
  • dc.date.accessioned 2021-07-23T06:57:08Z
  • dc.date.available 2021-07-23T06:57:08Z
  • dc.date.issued 2021
  • dc.description.abstract Background: 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. Methods: 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). Results: 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-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. Conclusions: 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.
  • dc.description.sponsorship This work was supported by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI17/00950, M.C., PI18/01392, P.A. and PI17/00943, F.B.) and co-financed by the European Regional Development Fund (ERDF) and Fundación Asociación Española Contra el Cáncer (M.C. and P.A.), Gilead Fellowships (GLD16/00144, GLD18/00047, F.B.) and Fundació la Marató de TV3 (201905–30-31 F.B). S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero. R.V-M. is supported by a Torres Quevedo fellowship from the Spanish Ministry of Science and Innovation (PTQ-16-08623). A.E-C. is funded by ISCIII/MINECO (PT17/0009/0019) which is co-funded by FEDER. M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-2018)
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Jiménez I, Tazón-Vega B, Abrisqueta P, Nieto J C, Bobillo S, Palacio-García C et al. Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia. Biomark Res. 2021 May 20;9(1):37. DOI: 10.1186/s40364-021-00290-z
  • dc.identifier.doi http://dx.doi.org/10.1186/s40364-021-00290-z
  • dc.identifier.issn 2050-7771
  • dc.identifier.uri http://hdl.handle.net/10230/48280
  • dc.language.iso eng
  • dc.publisher BioMed Central
  • dc.rights © Isabel Jiménez et al. 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Leucèmia
  • dc.subject.other Immunologia
  • dc.subject.other Genètica
  • dc.title Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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