Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients

Franziska Blaeschke, Semjon Willier, Dana Stenger, Mareike Lepenies, Martin A. Horstmann, Gabriele Escherich, Martin Zimmermann, Francisca Rojas Ringeling, Stefan Canzar, Theresa Kaeuferle, Meino Rohlfs, Vera Binder, Christoph Klein, Tobias Feuchtinger

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Interaction of malignancies with tissue-specific immune cells has gained interest for prognosis and intervention of emerging immunotherapies. We analyzed bone marrow T cells (bmT) as tumor-infiltrating lymphocytes in pediatric precursor-B cell acute lymphoblastic leukemia (ALL). Based on data from 100 patients, we show that ALL is associated with late-stage CD4+ phenotype and loss of early CD8+ T cells. The inhibitory exhaustion marker TIM-3 on CD4+ bmT increased relapse risk (RFS = 94.6/70.3%) confirmed by multivariate analysis. The hazard ratio of TIM-3 expression nearly reached the hazard ratio of MRD (7.1 vs. 8.0) indicating that patients with a high frequency of TIM-3+CD4+ bone marrow T cells at initial diagnosis have a 7.1-fold increased risk to develop ALL relapse. Comparison of wild type primary T cells to CRISPR/Cas9-mediated TIM-3 knockout and TIM-3 overexpression confirmed the negative effect of TIM-3 on T cell responses against ALL. TIM-3+CD4+ bmT are increased in ALL overexpressing CD200, that leads to dysfunctional antileukemic T cell responses. In conclusion, TIM-3-mediated interaction between bmT and leukemia cells is shown as a strong risk factor for relapse in pediatric B-lineage ALL. CD200/TIM-3-signaling, rather than PD-1/PD-L1, is uncovered as a mechanism of T cell dysfunction in ALL with major implication for future immunotherapies.

Original languageEnglish (US)
Pages (from-to)2607-2620
Number of pages14
JournalLeukemia
Volume34
Issue number10
DOIs
StatePublished - Oct 1 2020

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

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