Marta Crespo1,2, Francesc Bosch3,4, Isabel Jiménez1,2, Bárbara Tazón-Vega2,5, Pau Abrisqueta2,5, Juan C Nieto1,2, Sabela Bobillo2,5, Carles Palacio-García2,5, Júlia Carabia1,2, Rafael Valdés-Mas6, Magdalena Munuera1,2, Lluís Puigdefàbregas1,2, Genís Parra7,8, Anna Esteve-Codina7,8, Clara Franco-Jarava9, Gloria Iacoboni2,5, María José Terol10, José Antonio García-Marco11. 1. Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/Natzaret 115-117, 08035, Barcelona, Spain. 2. Department de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain. 3. Department de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain. fbosch@vhio.net. 4. 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. fbosch@vhio.net. 5. 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. 6. DREAMgenics, 33011, Oviedo, Spain. 7. Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08003, Barcelona, Spain. 8. Universitat Pompeu Fabra, 08002, Barcelona, Spain. 9. 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. 10. Department of Hematology, Clínic University Hospital, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain. 11. Department of Hematology, Puerta de Hierro University Hospital, 28222, Majadahonda, Madrid, Spain.
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.
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.
Entities:
Keywords:
CLL; Clinical progression; Immune evasion; T cell exhaustion
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