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

Biomarker Research

Genís Parra¹  Anna Esteve-Codina¹  Rafael Valdés-Mas²  Carles Palacio-García³  Sabela Bobillo³  Bárbara Tazón-Vega³  Gloria Iacoboni³  Francesc Bosch³  Pau Abrisqueta³  María José Terol⁴  José Antonio García-Marco⁵  Magdalena Munuera⁶  Lluís Puigdefàbregas⁶  Isabel Jiménez⁶  Júlia Carabia⁶  Marta Crespo⁶  Juan C. Nieto⁶  Clara Franco-Jarava⁷ 

[1] Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08003, Barcelona, Spain;Universitat Pompeu Fabra, 08002, Barcelona, Spain;DREAMgenics, 33011, Oviedo, Spain;Department de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain;Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain;Department of Hematology, Clínic University Hospital, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain;Department of Hematology, Puerta de Hierro University Hospital, 28222, Majadahonda, Madrid, Spain;Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, C/Natzaret 115-117, 08035, Barcelona, Spain;Department de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain;Servei d’Immunologia, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain;

关键词: CLL;    Immune evasion;    Clinical progression;    T cell exhaustion;   

DOI  :  10.1186/s40364-021-00290-z

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY