T-Cell Dynamics in Chronic Lymphocytic Leukemia under Different Treatment Modalities.
Clin Cancer Res
; 26(18): 4958-4969, 2020 09 15.
Article
en En
| MEDLINE
| ID: mdl-32616500
ABSTRACT
PURPOSE:
Using next-generation sequencing (NGS), we recently documented T-cell oligoclonality in treatment-naïve chronic lymphocytic leukemia (CLL), with evidence indicating T-cell selection by restricted antigens. EXPERIMENTALDESIGN:
Here, we sought to comprehensively assess T-cell repertoire changes during treatment in relation to (i) treatment type [fludarabine-cyclophosphamide-rituximab (FCR) versus ibrutinib (IB) versus rituximab-idelalisib (R-ID)], and (ii) clinical response, by combining NGS immunoprofiling, flow cytometry, and functional bioassays.RESULTS:
T-cell clonality significantly increased at (i) 3 months in the FCR and R-ID treatment groups, and (ii) over deepening clinical response in the R-ID group, with a similar trend detected in the IB group. Notably, in constrast to FCR that induced T-cell repertoire reconstitution, B-cell receptor signaling inhibitors (BcRi) preserved pretreatment clones. Extensive comparisons both within CLL as well as against T-cell receptor sequence databases showed little similarity with other entities, but instead revealed major clonotypes shared exclusively by patients with CLL, alluding to selection by conserved CLL-associated antigens. We then evaluated the functional effect of treatments on T cells and found that (i) R-ID upregulated the expression of activation markers in effector memory T cells, and (ii) both BcRi improved antitumor T-cell immune synapse formation, in marked contrast to FCR.CONCLUSIONS:
Taken together, our NGS immunoprofiling data suggest that BcRi retain T-cell clones that may have developed against CLL-associated antigens. Phenotypic and immune synapse bioassays support a concurrent restoration of functionality, mostly evident for R-ID, arguably contributing to clinical response.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Linfocitos T
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Leucemia Prolinfocítica de Células T
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Protocolos de Quimioterapia Combinada Antineoplásica
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Sinapsis Inmunológicas
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Evolución Clonal
Tipo de estudio:
Clinical_trials
/
Etiology_studies
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Incidence_studies
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Observational_studies
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Risk_factors_studies
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2020
Tipo del documento:
Article