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TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression

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Abstract

In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H2O2 in a contact-dependent mechanism, thereby inducing a lethal Ca2+ influx via the activation of the H2O2-dependent TRPM2 Ca2+ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanisms—downregulation of neutrophil chemoattractants and blocking of the apoptotic Ca2+-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

ATCC:

American Type Culture Collection

CXCL1:

Chemokine (C-X-C motif) ligand 1

CXCL2:

Chemokine (C-X-C motif) ligand 2

CXCL5:

Chemokine (C-X-C motif) ligand 5

CXCL12:

Chemokine (C-X-C motif) ligand 12

CXCR2:

Chemokine receptor type 2

IL1β:

Interleukin 1 beta

IL6:

Interleukin 6

MET:

Mesenchymal–epithelial transition tyrosine kinase receptor

NDN:

Normal density neutrophils

qPCR:

Quantitative real-time PCR

TRPM2:

Transient receptor potential melastatin 2

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Funding

Zvi Granot was supported by Grants from the I-CORE Gene Regulation in Complex Human Disease, Center no. 41/11, the Israel Science Foundation (756/15), the Israel Cancer Research Foundation (RCDA), The Rosetrees Trust, and the Israel Cancer Association.

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Authors and Affiliations

  1. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University Medical School, Ein Kerem, 91120, Jerusalem, Israel

    Maya Gershkovitz, Tanya Fainsod-Levi, Tamir Zelter, Ronit V. Sionov & Zvi Granot

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  1. Maya Gershkovitz
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  2. Tanya Fainsod-Levi
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  3. Tamir Zelter
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  4. Ronit V. Sionov
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Contributions

MG and ZG conceived and designed the experiments; MG, TFL, TZ, and RVS performed the experiments; ZG supervised the experiments; MG and ZG wrote the manuscript.

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Correspondence to Zvi Granot.

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Gershkovitz, M., Fainsod-Levi, T., Zelter, T. et al. TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression. Cancer Immunol Immunother 68, 33–43 (2019). https://doi.org/10.1007/s00262-018-2249-2

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