Natural Killer Cell–Mediated Cytotoxicity Shapes the Clonal Evolution of B-cell Leukemia

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumor growth and is divided into three phases: elimination, equilibrium, and escape. The role of NK cells has mainly been attributed to the elimination phase. Here, we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA-barcoded mouse BCR/ABLp185+ B-cell acute lymphoblastic leukemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Although most tumor cell clones were efficiently eliminated by NK cells, a certain fraction of tumor cells harbored an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumor cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell-mediated cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumor cell clones, which were characterized by an IFNγ signature. Besides well-known regulators of immune evasion, our analysis of NK cell-resistant tumor cells revealed the upregulation of genes, including lymphocyte antigen 6 complex, locus A (Ly6a), which we found to promote leukemic cell resistance to NK cells. Translation of our findings to the human system showed that high expression of LY6E on tumor cells impaired their physical interaction with NK cells and led to worse prognosis in patients with leukemia. Our results demonstrate that tumor cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.

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Publication Details

Journal
Cancer Immunology Research
Published
2024-12-06
DOI
https://doi.org/10.1158/2326-6066.cir-24-0189
Citations
2
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.48

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article

Natural Killer Cell–Mediated Cytotoxicity Shapes the Clonal Evolution of B-cell Leukemia

Ton N. Schumacher, Jason Cosgrove, Florian Halbritter, Manfred Lehner et al.
2 citations
Cancer Immunology Research
Immune Cell Function and Interaction
0.48
article

Natural Killer Cell–Mediated Cytotoxicity Shapes the Clonal Evolution of B-cell Leukemia

Ton N. Schumacher, Jason Cosgrove, Florian Halbritter, Manfred Lehner, Dominik Emminger, Aleksandr Bykov, Peter Repiščák, Anna R. Poetsch, Dagmar Schinnerl, Xaver Koenig, Mohamed R. Shoeb, Boris Kovačic, Faith Hall‐Glenn, Jos H. M. Urbanus, Leïla Perié, Michelle C. Buri, Hayeon Baik, Dagmar Gotthardt, Lisa Sippl, Alma Dupanovic, Faith O. David, Eva M. Putz, Sara Dopa, Susanne Stofner
article en
2 citations

Abstract

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumor growth and is divided into three phases: elimination, equilibrium, and escape. The role of NK cells has mainly been attributed to the elimination phase. Here, we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA-barcoded mouse BCR/ABLp185+ B-cell acute lymphoblastic leukemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Although most tumor cell clones were efficiently eliminated by NK cells, a certain fraction of tumor cells harbored an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumor cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell-mediated cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumor cell clones, which were characterized by an IFNγ signature. Besides well-known regulators of immune evasion, our analysis of NK cell-resistant tumor cells revealed the upregulation of genes, including lymphocyte antigen 6 complex, locus A (Ly6a), which we found to promote leukemic cell resistance to NK cells. Translation of our findings to the human system showed that high expression of LY6E on tumor cells impaired their physical interaction with NK cells and led to worse prognosis in patients with leukemia. Our results demonstrate that tumor cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.

Cancer Immunology ResearchVol. 13(3)
Centre National de la Recherche Scientifique (FR), University of Veterinary Medicine Vienna (AT), Université Paris Sciences et Lettres (FR), Dutch Cancer Society (NL), Leiden University Medical Center (NL), The Netherlands Cancer Institute (NL), Sorbonne Université (FR), Christian Doppler Laboratory for Thermoelectricity (AT), Oncode Institute (NL), St Anna Children's Hospital (AT), Center for Systems Biology Dresden (DE), Physique des Cellules et Cancers (FR), St. Anna Children's Cancer Research Institute, Community College of Rhode Island (US), Medical University of Vienna (AT), Technische Universität Dresden (DE), Institut Curie (FR)
Cancer Research Institute, Alex's Lemonade Stand Foundation for Childhood Cancer, Österreichischen Akademie der Wissenschaften, Austrian Science Fund, Universität Wien, Medizinische Universität Wien, Deutsche Krebshilfe, Veterinärmedizinische Universität Wien
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Openalex Percentile: Top 33%
Immune Cell Function and Interaction
0.48
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