T-Cell Dynamics in Chronic Lymphocytic Leukemia under Different Treatment Modalities

Anna Vardi, Elisavet Vlachonikola, Despoina Papazoglou, Fotis Psomopoulos, Kostantia Kotta, Nikolaos Ioannou, Chrysi Galigalidou, Katerina Gemenetzi, Kostantinos Pasentsis, Maria Kotouza, Evdoxia Koravou, Lydia Scarfo, Michail Iskas, Niki Stavroyianni, Paolo Ghia, Achilles Anagnostopoulos, Anastasia Kouvatsi, Alan G. Ramsay, Kostas Stamatopoulos, Anastasia Chatzidimitriou

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Using next-generation sequencing (NGS), we recently documented T-cell oligoclonality in treatment-nave chronic lymphocytic leukemia (CLL), with evidence indicating T-cell selection by restricted antigens. Experimental Design: 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.

Original languageEnglish
Pages (from-to)4958-4969
Number of pages12
JournalClinical Cancer Research
Volume26
Issue number18
DOIs
Publication statusPublished - Sep 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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