Isolation and Characterization of Neutrophils with Anti-Tumor Properties

Sionov, Ronit Vogt; Assi, Simaan; Gershkovitz, Maya; Sagiv, Jitka Yehudith; Polyansky, Lola; Mishalian, Inbal; Fridlender, Zvi G.; Granot, Zvi

doi:10.3791/52933

Cited by 33 publications

(36 citation statements)

References 21 publications

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“…Therefore, high expression of granulocytic chemokines may result in strong infiltration of neutrophils in the tumor microenvironment. Activated neutrophils are known to have some antitumor activity (Challacombe et al, 2006; Sionov et al, 2015), and their massive recruitment may be detrimental for tumors.…”

Section: Discussionmentioning

confidence: 99%

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

et al. 2017

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Summary Tumor associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited antitumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated down-regulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this cross talk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.

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Section: Discussionmentioning

confidence: 99%

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

et al. 2017

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“…Depletion of such neutrophils, or suppression of their migration, leads to significant abrogation of tumorigenesis in mice . On the other hand, tumor microenvironment can also prime antitumor properties of neutrophils, leading to suppression of tumor growth and metastasis by these cells . Such plasticity of neutrophils provides a potential target for therapies that enhance their antitumor activity while limiting protumor functions.…”

mentioning

confidence: 99%

NAMPT signaling is critical for the proangiogenic activity of tumor‐associated neutrophils

Pylaeva

Harati

Spyra

et al. 2018

Intl Journal of Cancer

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Tumor-associated neutrophils (TANs) regulate many processes associated with tumor progression, and depending on the microenvironment, they can exhibit pro- or antitumor functions. However, the molecular mechanisms regulating their tumorigenicity are not clear. Using transplantable tumor models, we showed here that nicotinamide phosphoribosyltransferase (NAMPT), a molecule involved in CSF3R downstream signaling, is essential for tumorigenic conversion of TANs and their pro-angiogenic switch. As a result tumor vascularization and growth are strongly supported by these cells. Inhibition of NAMPT in TANs leads to their antitumor conversion. Adoptive transfer of such TANs into B16F10-tumor bearing mice attenuates tumor angiogenesis and growth. Of note, we observe that the regulation of NAMPT signaling in TANs, and its effect on the neutrophil tumorigenicity, are analogous in mice and human. NAMPT is up-regulated in TANs from melanoma and head-and-neck tumor patients, and its expression positively correlates with tumor stage. Mechanistically, we found that targeting of NAMPT suppresses neutrophil tumorigenicity by inhibiting SIRT1 signaling, thereby blocking transcription of pro-angiogenic genes. Based on these results, we propose that NAMPT regulatory axis is important for neutrophils to activate angiogenic switch during early stages of tumorigenesis. Thus, identification of NAMPT as the critical molecule priming protumor functions of neutrophils provides not only mechanistic insight into the regulation of neutrophil tumorigenicity, but also identifies a potential pathway that may be targeted therapeutically in neutrophils. This, in turn, may be utilized as a novel mode of cancer immunotherapy.

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“…Neutrophils were purified from orthotopically injected (mammary fat pad) 3-week 4T1 tumorbearing mice as described before (Sionov et al, 2015a). In brief, whole blood was collected by cardiac puncture using heparinized (Sigma) syringe.…”

Section: Neutrophil Purificationmentioning

confidence: 99%

The pd-l1/pd-1 axis blocks neutrophil cytotoxicity in cancer

Gershkovitz

Yajuk

Fainsod-Levi

et al. 2020

Preprint

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The PD-L1/PD-1 axis was shown to promote tumor growth and progression via the inhibition of anti-tumor immunity. Blocking this axis was shown to be beneficial in maintaining the antitumor functions of the adaptive immune system. Still, the consequences of blocking the PD-L1/PD-1 axis on innate immune responses remain largely unexplored. In this context, neutrophils were shown to consist of different subpopulations, which possess either pro-and anti-tumor properties. PD-L1-expressing neutrophils are considered pro-tumor as they can suppress cytotoxic T-cells. That said, we found that PD-L1 expression is not limited to tumor promoting neutrophils but is also evident in anti-tumor neutrophils. We show that neutrophil cytotoxicity is effectively and efficiently blocked by tumor cell expressed PD-1. Furthermore blocking of either neutrophil PD-L1 or tumor cell PD-1 maintains neutrophil cytotoxicity resulting in enhanced tumor cell apoptosis. Importantly, we show that tumor cell PD-1 blocks neutrophil cytotoxicity and promotes tumor growth via a mechanism independent of adaptive immunity. Taken together, these findings highlight the therapeutic potential of enhancing anti-tumor innate immune responses via blocking of the PD-L1/PD-1 axis.

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Isolation and Characterization of Neutrophils with Anti-Tumor Properties

Cited by 33 publications

References 21 publications

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

NAMPT signaling is critical for the proangiogenic activity of tumor‐associated neutrophils

The pd-l1/pd-1 axis blocks neutrophil cytotoxicity in cancer

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