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

Blaeschke, Franziska; Willier, Semjon; Stenger, Dana; Lepenies, Mareike; Horstmann, Martin A.; Escherich, Gabriele; Zimmermann, Martin; Ringeling, Francisca Rojas; Canzar, Stefan; Kaeuferle, Theresa; Rohlfs, Meino; Binder, Vera; Klein, Christoph and Feuchtinger, Tobias (2020): Leukemia-induced dysfunctional TIM-3(+)CD4(+) bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients. In: Leukemia, Vol. 34, No. 10: pp. 2607-2620

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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0887-6924
• Language: English