Cancer-promoting mechanisms of tumor-associated neutrophils

Highlights

• A phenotypically distinct population of neutrophils, called Tumor Associated Neutrophils (TANs) have been shown to be recruited into solid tumors, where the functions of TANs is modified and coapted to aid in tumor progression.

• This review focuses on these mechanisms mediating cancer progression and then discusses the potential role of surgically-based adjuvant therapy in loco-regional targeting of these pro-cancer mechanisms.

Abstract

Importance

Neutrophils have classically been considered to mount a defensive response against tumor cells, yet recent evidence suggests tumors modulate neutrophil function to support tumor growth and progression.

Observations

Tumor-associated neutrophils (TANs) are phenotypically distinct from circulating neutrophils in terms of their surface protein composition and cyto/chemokine activity and response. Although TANs have been shown to both promote and inhibit tumor advancement, the preponderant activity augments tumor progression. This review discusses these cancer-promoting molecular pathways, relevant diagnostic studies in patients, and subsequent treatment modalities.

The tumor promoting mechanisms of TANs include dampening of CD8⁺ response via Arginase-1; a neutrophil-secreted neutrophil elastase (NE) upregulation of tumor cellular proliferation pathways; degradation of basement membrane and ECM via NE and MMP-9; upregulation of angiogenesis by VEGF, and HGF; and ICAM-1 dependent tumor intravasation, immune protection in circulation, and extravasation into distant, metastatic tissue beds.

Clinicians are constrained in treating TANs systemically as it may induce neutropenia, therefore targeting TANs-mediated tumor progression pathways surgically on a loco-regional level is a viable adjuvant treatment modality.

Conclusion and relevance

TANs modulate the tumor microenvironment promoting tumor progression. Mechanistic understanding of TANs role in tumor progression will provide unique therapeutic alternatives.

Introduction

There is continuous crosstalk between cancer cells, stromal cells, and the immune system in the tumor microenvironment.¹ Infiltrating neutrophils are found in many solid tumors, where they were classically considered indicative of a defensive immune response,2, 3, 4 however there is substantial evidence demonstrating neutrophils, via paracrine modulation, promote local tumor growth and play an active role in tumor progression to distant metastasis.5, 6, 7, 8, 9, 10

A recent study illustrates tumor cells induce unique phenotypic changes in peripheral blood monocytes into myeloid-derived suppressor cells (MDSC).¹⁰ These changes include expression of myeloid derived CD11b+, CD33⁺, CD66+.11, 12, 13 MDSCs have been shown to enter tumors and differentiate into tumor-associated neutrophils (TANs),¹⁴ which differ epigenetically and functionally from naïve, or classically defined, neutrophils. Transcriptome analysis between naïve neutrophils, MDSCs, and TANs shows that both TANs and MDSCs transcribe higher amounts of cytokine and chemokine mRNA (ICAM-1, CXCL-1 and 2, and CCL-17) than circulating neutrophils.¹⁵

TANs refer to a tumor-dependent, heterogeneous group of neutrophils which are sub-classified, similar to that of tumor-associated macrophages, based on their anti- or pro-tumor properties, known as N1 and N2, respectively.¹⁶ Recent experiments in murine lung cancer demonstrate that intra-tumor neutrophils initially display an anti-tumor phenotype- (N1) and as the tumor progresses TANs become distributed within the tumor and take on a pro-tumor phenotype (N2).¹⁷ The N1 TANs create inflammation by secreting cytokines (IL-1β, TNF-α, IL-6, and IL-12) and reactive oxygen species acting to damage (tumor) cells.¹⁸ However, these functions are down-regulated as the tumor progresses and the N2 phenotype become predominant.¹⁷

This review outlines this complex longitudinal interaction between TANs and tumor cells, including the role of TANs in local progression, intravasation, extravasation and macroscopic metastases.