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


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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Antibody-dependent cellular cytotoxicity


American Type Culture Collection


Chemokine (C-X-C motif) ligand 1


Chemokine (C-X-C motif) ligand 2


Chemokine (C-X-C motif) ligand 5


Chemokine (C-X-C motif) ligand 12


Chemokine receptor type 2


Interleukin 1 beta


Interleukin 6


Mesenchymal–epithelial transition tyrosine kinase receptor


Normal density neutrophils


Quantitative real-time PCR


Transient receptor potential melastatin 2


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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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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).

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  • Neutrophils
  • TRPM2
  • CXCL2
  • Immune evasion