Neutrophil Heterogeneity in Cancer: From Biology to Therapies

Abstract

Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.

Keywords: G-MDSC (granulocytic MDSC); MDSC (myeloid-derived suppressor cells); cancer; immunotherapy; neutrophil (PMN); subsets; tumor-associated neutrophils (TANs).

Figure 1

(A) This figure reviews studies supporting the improved or worsened prognostic impact of TANs in situ at early (stage I and stage II; stage II alone) and late-stage (stage III; stage III and IV) of tumorigenesis across different cancer types. Quantification neutrophils based on a particular location in situ was precised (intratumoral, tumor front, and peritumoral). Neutrophil markers used for identification of neutrophils in situ by immunostaining were either CD66b or Arginase. Others identified neutrophils in situ based on their morphology through Hematoxylin and Eosin (H&E) staining. Patient prognostic impact was assessed based on overall survival (OS), disease-free survival (DFS), and cancer specific survival (CSS). Light gray background refers to early-stage tumors whereas dark gray background points out late-stage tumors. Abbreviations were used for the cancer type column: CRC, Colorectal cancer; SKCM, Skin Cutaneous Melanoma; Cervical SCC, Cervical squamous cell carcinoma; HNSCC, Head and Neck squamous cell carcinoma. (B) This figure covers studies ex-vivo functional analysis supporting the anti-tumor or pro-tumor role of neutrophils in early (stage I and II) or late-stage (stage III and IV) of tumorigenesis in various cancer types. This figure includes markers expressed at protein level by anti-tumor or pro-tumor neutrophils. Light gray background refers to early-stage tumors whereas dark gray background points out late-stage tumors. White background was set for unknown tumor stage. Abbreviations were used for the cancer type column: NSCLC, Non-small-cell lung carcinoma; CRC, Colorectal cancer.

Figure 2

This figure summarizes the different neutrophil-based therapeutic strategies with various mechanisms of action described in bone marrow, blood and tumor. In green: prevention of neutrophil exit from bone marrow and entry to tumor tissue. In gray: depletion of neutrophils. In red: inhibition of the T-cell suppressive functions of neutrophils. In blue: prevention of neutrophil capacity to foster tumor cell proliferation and migration. In purple: promotion of the anti-tumor functions of neutrophils.