transfer-manipulated-tumor-associated-neutrophils-into-tumor-bearing

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

The contribution of neutrophils to the regulation of tumorigenesis is getting increased attention. These cells are heterogeneous, and depending on the ...

University of Duisburg-Essen

The importance of tumor associated neutrophils (TANs) in cancer development is in the meantime well established. Numerous of clinical data document the adverse prognostic effects of neutrophil infiltration in solid tumors. However, certain tumor therapies need functional neutrophils to be effective, suggesting altered neutrophil polarization associated with different outcomes for cancer patients. Therefore, modulation of neutrophilic phenotypes represents a potent therapeutic option, but factors mediating neutrophil polarization are still poorly defined. In this manuscript we provide evidence that type I IFNs alter neutrophilic phenotype into anti-tumor, both in mice and human. In the absence of IFN-β, pro-tumor properties, such as reduced tumor cytotoxicity with low neutrophil extracellular traps (NETs) expression, low ICAM1 and TNF-α expression, dominated neutrophil phenotypes in primary lesion and premetastatic lung. Interestingly, such neutrophils have significantly prolonged life-span. Notably, interferon therapy in mice altered TAN polarization towards anti-tumor N1. Similar changes in neutrophil activation could be observed in melanoma patients undergoing type I IFN therapy. Altogether, these data highlight the therapeutic potential of interferons, suggesting optimization of its clinical use as potent anti-tumor agent.

Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human.

The importance of endogenous Type I IFNs in cancer immune surveillance is well established by now. Their role in polarization of tumor-associated neutrophilic granulocytes into anti-tumor effector cells has been recently demonstrated. Yet, the cellular source of Type I IFNs as well as the mode of induction is not clearly defined. Here, we demonstrate that IFN-β is induced by growing murine tumors. Induction is mainly mediated via STING-dependent signaling pathways, suggesting tumor derived DNA as trigger. Transcription factors IRF3 and IRF5 were activated under these conditions which is consistent with tumor infiltrating dendritic cells (DCs) being the major cellular source of IFN-β at the tumor site. Besides DCs, tumor cells themselves are induced to contribute to the production of IFN-β. Taken together, our data provide further information on immune surveillance by Type I IFNs and suggest novel potent cellular targets for future cancer therapy.

Growing tumors induce a local STING dependent Type I IFN response in dendritic cells.

Neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells with very defined roles in inflammation and fighting infections. However, recent advances in neutrophil research challenge this limited view and demonstrate that neutrophils are highly versatile, play different roles in various pathologic scenarios, and are heterogeneous. With this, it is becoming clear that one term-"neutrophil"-is too general, and more precise nomenclature is urgently required. In this mini review, we discuss the knowns and unknowns in neutrophil terminology and highlight the critical questions that should be addressed for the establishment of clear neutrophil nomenclature.

Neutrophil, quo vadis?

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.

Article	Year
Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. International journal of cancer\| PubMed ID: 26619320	2016
Growing tumors induce a local STING dependent Type I IFN response in dendritic cells. International journal of cancer\| PubMed ID: 27116225	2016
Neutrophil, quo vadis? Journal of leukocyte biology\| PubMed ID: 28360185	2017
NAMPT signaling is critical for the proangiogenic activity of tumor-associated neutrophils. International journal of cancer\| PubMed ID: 30121947	2019

Jadwiga Jablonska

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