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

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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; Rojas Ringeling, Francisca; Canzar, Stefan; Kaeuferle, Theresa; Rohlfs, Meino; Binder, Vera; Klein, Christoph; Feuchtinger, Tobias.

In: LEUKEMIA, Vol. 34, No. 10, 10.2020, p. 2607-2620.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Blaeschke, F, Willier, S, Stenger, D, Lepenies, M, Horstmann, MA, Escherich, G, Zimmermann, M, Rojas Ringeling, F, Canzar, S, Kaeuferle, T, Rohlfs, M, Binder, V, Klein, C & Feuchtinger, T 2020, 'Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients', LEUKEMIA, vol. 34, no. 10, pp. 2607-2620. https://doi.org/10.1038/s41375-020-0793-1

APA

Blaeschke, F., Willier, S., Stenger, D., Lepenies, M., Horstmann, M. A., Escherich, G., Zimmermann, M., Rojas Ringeling, F., Canzar, S., Kaeuferle, T., Rohlfs, M., Binder, V., Klein, C., & Feuchtinger, T. (2020). Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients. LEUKEMIA, 34(10), 2607-2620. https://doi.org/10.1038/s41375-020-0793-1

Vancouver

Blaeschke F, Willier S, Stenger D, Lepenies M, Horstmann MA, Escherich G et al. Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients. LEUKEMIA. 2020 Oct;34(10):2607-2620. https://doi.org/10.1038/s41375-020-0793-1

Bibtex

@article{d9b4d2068eb045c881a1467dc7a98ffa,
title = "Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients",
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.",
keywords = "Adolescent, Biomarkers, Tumor, Bone Marrow Cells/immunology, CD4 Antigens/immunology, Child, Child, Preschool, Female, Hepatitis A Virus Cellular Receptor 2/immunology, Humans, Infant, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology, Prognosis, Recurrence, Risk Factors",
author = "Franziska Blaeschke and Semjon Willier and Dana Stenger and Mareike Lepenies and Horstmann, {Martin A} and Gabriele Escherich and Martin Zimmermann and {Rojas Ringeling}, Francisca and Stefan Canzar and Theresa Kaeuferle and Meino Rohlfs and Vera Binder and Christoph Klein and Tobias Feuchtinger",
year = "2020",
month = oct,
doi = "10.1038/s41375-020-0793-1",
language = "English",
volume = "34",
pages = "2607--2620",
journal = "LEUKEMIA",
issn = "0887-6924",
publisher = "NATURE PUBLISHING GROUP",
number = "10",

}

RIS

TY - JOUR

T1 - Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients

AU - Blaeschke, Franziska

AU - Willier, Semjon

AU - Stenger, Dana

AU - Lepenies, Mareike

AU - Horstmann, Martin A

AU - Escherich, Gabriele

AU - Zimmermann, Martin

AU - Rojas Ringeling, Francisca

AU - Canzar, Stefan

AU - Kaeuferle, Theresa

AU - Rohlfs, Meino

AU - Binder, Vera

AU - Klein, Christoph

AU - Feuchtinger, Tobias

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

KW - Adolescent

KW - Biomarkers, Tumor

KW - Bone Marrow Cells/immunology

KW - CD4 Antigens/immunology

KW - Child

KW - Child, Preschool

KW - Female

KW - Hepatitis A Virus Cellular Receptor 2/immunology

KW - Humans

KW - Infant

KW - Male

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology

KW - Prognosis

KW - Recurrence

KW - Risk Factors

U2 - 10.1038/s41375-020-0793-1

DO - 10.1038/s41375-020-0793-1

M3 - SCORING: Journal article

C2 - 32203137

VL - 34

SP - 2607

EP - 2620

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 10

ER -