Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFα and NO-dependent mechanism, promoting a tumor-supportive environment

Janna Michaeli, Merav E. Shaul, Inbal Mishalian, Avi Hai Hovav, Liran Levy, Lidia Zolotriov, Zvi Granot, Zvi G. Fridlender*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

The role of neutrophils in tumor progression has become in recent years a subject of growing interest. Tumor-associated neutrophils (TANs), which constitute an important portion of the tumor microenvironment, promote immunosuppression in advanced tumors by modulating the proliferation, activation and recruitment of a variety of immune cell types. Studies which investigated the consequences of manipulating TAN polarization suggest that the impact of these neutrophils on tumor progression is considerably mediated by and dependent on the presence of CD8 T-cells. It has been previously shown that granulocytic myeloid regulatory cells, i.e. TANs and granulocytic myeloid-derived suppressor cells (G-MDSCs) are capable of suppressing CD8 T-cell proliferation and affect their activation. In the current study, we find that in addition, TANs isolated from different models of murine cancer promote immunosuppression by strongly inducing CD8 T-cell apoptosis. We demonstrate that the TNFα pathway in TANs is critical for the induction of apoptosis, and that the mechanism through which apoptosis is induced involves the production of NO, but not ROS. In the absence of pre-activation, TANs are capable of activating CD8 T-cells, but specifically induce the apoptosis of non-activated CD8+CD69 cells. Despite this contradictive effect on T-cell function, we show in vivo that TANs suppress the anti-tumor effect of CD8 T-cells and abolish their ability to delay tumor growth. Our results add another important layer on the understanding of the possible mechanisms by which TANs regulate the anti-tumor immune response mediated by CD8 T-cells, therefore promoting a tumor-supportive environment.

Original languageAmerican English
Article numbere1356965
JournalOncoImmunology
Volume6
Issue number11
DOIs
StatePublished - 2 Nov 2017

Bibliographical note

Publisher Copyright:
© 2017 Taylor & Francis Group, LLC.

Keywords

  • Activation
  • CD8 cytotoxic T-cell
  • apoptosis
  • immunotolerance
  • lung cancer
  • tumor-associated neutrophils

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