T cell repertoire in patients with B chronic lymphocytic leukemia. Evidence for multiple in vivo T cell clonal expansions.

Farace, Françoise; Orlanducci, Florence; Dietrich, Pierre‐Yves; Gaudin, Catherine; Angevin, Eric; Courtier, Marie Hélène; Bayle, C; Hercend, Thierry; Triebel, Frédéric

doi:10.4049/jimmunol.153.9.4281

Cited by 96 publications

(2 citation statements)

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“…In keeping with the literature, all cases of the present study displayed an oligoclonal TR repertoire, regardless of the underlying genomic background ( 13 , 14 , 16 , 17 ). However, cases bearing CNAs, particularly those with trisomy 12, presented with more pronounced repertoire skewing compared to cases bearing isolated TP53 or NOTCH1 mutations.…”

Section: Discussionsupporting

confidence: 90%

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T cell receptor gene repertoire profiles in subgroups of patients with chronic lymphocytic leukemia bearing distinct genomic aberrations

Vlachonikola

Pechlivanis²,

Karakatsoulis³

et al. 2023

Front. Oncol.

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BackgroundMicroenvironmental interactions of the malignant clone with T cells are critical throughout the natural history of chronic lymphocytic leukemia (CLL). Indeed, clonal expansions of T cells and shared clonotypes exist between different CLL patients, strongly implying clonal selection by antigens. Moreover, immunogenic neoepitopes have been isolated from the clonotypic B cell receptor immunoglobulin sequences, offering a rationale for immunotherapeutic approaches. Here, we interrogated the T cell receptor (TR) gene repertoire of CLL patients with different genomic aberration profiles aiming to identify unique signatures that would point towards an additional source of immunogenic neoepitopes for T cells.Experimental designTR gene repertoire profiling using next generation sequencing in groups of patients with CLL carrying one of the following copy-number aberrations (CNAs): del(11q), del(17p), del(13q), trisomy 12, or gene mutations in TP53 or NOTCH1.ResultsOligoclonal expansions were found in all patients with distinct recurrent genomic aberrations; these were more pronounced in cases bearing CNAs, particularly trisomy 12, rather than gene mutations. Shared clonotypes were found both within and across groups, which appeared to be CLL-biased based on extensive comparisons against TR databases from various entities. Moreover, in silico analysis identified TR clonotypes with high binding affinity to neoepitopes predicted to arise from TP53 and NOTCH1 mutations.ConclusionsDistinct TR repertoire profiles were identified in groups of patients with CLL bearing different genomic aberrations, alluding to distinct selection processes. Abnormal protein expression and gene dosage effects associated with recurrent genomic aberrations likely represent a relevant source of CLL-specific selecting antigens.

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Section: Discussionsupporting

confidence: 90%

“…Molecular studies by us and others revealed skewing of the TR repertoire and clonal expansions of T cells in CLL, supporting antigen drive ( 13 – 15 ). Moreover, different patients were found to share TR clonotypes, many of which were ‘CLL-biased’ i.e.…”

Section: Introductionmentioning

confidence: 59%

T cell receptor gene repertoire profiles in subgroups of patients with chronic lymphocytic leukemia bearing distinct genomic aberrations

Vlachonikola

Pechlivanis²,

Karakatsoulis³

et al. 2023

Front. Oncol.

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Chronic myeloid leukemia as an immunological target

Lim

Coleman

1997

Am. J. Hematol.

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Various clinical observations have implicated T cells in the control of chronic myeloid leukemia (CML). These observations have in recent years been supported by laboratory results indicating the presence of CML-specific T cells in the lymphocyte repertoire of both normal healthy individuals and disease-bearing patients. Both MHC-unrestricted and MHC-restricted immune effector mechanisms are involved. Donor lymphocyte infusion has produced encouraging GvL effects. However, future adoptive immunotherapy may depend on the isolation and generation of leukemia-specific T cells. Although many proteins may potentially act as leukemia antigens in CML for MHC-restricted cytotoxicity, the bcr-abl fusion protein has been most extensively investigated. There is now much evidence to suggest that the bcr-abl junctional peptides are capable of eliciting both CD4 and CD8 responses in normal healthy donors and CML patients. Furthermore, the T-cell lines generated react with autologous or HLA-matched fresh CML cells, suggesting that the bcr-abl fusion protein can be processed in vivo so that the joining segment is bound to HLA molecules in a configuration and concentration similar to those of the immunizing peptide for antigen recognition by the antigen-specific T-cell receptor. These results also indicate that the bcr-abl junctional peptides may be used for immunotherapy of CML. Other strategies available for immunotherapy of CML include immunologically or genetically manipulated donor T-cell infusion, the use of cytokines, adoptive immunotherapy with leukemia-reactive T-cells expanded ex vivo, and immune gene therapy. Novel and rational immunotherapy may therefore play an important adjuvant role in future in the management of patients with CML.

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Altered pattern of cytokine production by peripheral blood CD2+ cells from B chronic lymphocytic leukemia patients

Reyes¹,

Prieto²,

Carrión³

et al. 1998

Am. J. Hematol.

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To determine if activation-induced cytokine production is altered in CD2+ lymphocytes from B-CLL patients, cytokine levels were determined by ELISA in supernatants of PHA-stimulated cultures of CD2+ cells from 33 B-CLL patients and 22 healthy controls. The production of Interferon gamma (IFN-gamma) and Tumor Necrosis Factor (TNF-alpha) by mitogen-activated CD2+ lymphocytes from B-CLL patients was higher than that found in healthy controls, while no differences were found in TNF-beta production. IFN-gamma and TNF-alpha levels determined at 72 h in PHA-stimulated CD2+ cell cultures from B-CLL patients statistically correlated with the percentages of CD3+CD45RO+ and CD3-CD56+ lymphocytes, respectively. Although there were differences in the production kinetics of interleukins (ILs) 2 and 4 between B-CLL patients and the healthy controls, no differences were found at the time when the levels of both interleukins peak. The production of both IFN-gamma and IL-4 by PHA-stimulated CD2+ lymphocytes from non-smouldering B-CLL patients was significantly higher than that from smouldering B-CLL patients while no significant differences were found in the production of IL-2, TNF-alpha, and TNF-beta between the two B-CLL patient groups. These data suggest that functional alterations in the production of cytokines by CD2+ cells from B-CLL patients could help to explain the expansion of leukemic cells in B-CLL patients.

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T cell repertoire in patients with B chronic lymphocytic leukemia. Evidence for multiple in vivo T cell clonal expansions.

Cited by 96 publications

References 0 publications

T cell receptor gene repertoire profiles in subgroups of patients with chronic lymphocytic leukemia bearing distinct genomic aberrations

T cell receptor gene repertoire profiles in subgroups of patients with chronic lymphocytic leukemia bearing distinct genomic aberrations

Chronic myeloid leukemia as an immunological target

Altered pattern of cytokine production by peripheral blood CD2+ cells from B chronic lymphocytic leukemia patients

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