N1 versus N2 and PMN‐MDSC: A critical appraisal of current concepts on tumor‐associated neutrophils and new directions for human oncology

Abstract

Summary Research on tumor‐associated neutrophils (TAN) currently surges because of the well‐documented strong clinical relevance of tumor‐infiltrating neutrophils. This relevance is illustrated by strong correlations between high frequencies of intratumoral neutrophils and poor outcome in the majority of human cancers. Recent high‐dimensional analysis of murine neutrophils provides evidence for unexpected plasticity of neutrophils in murine models of cancer and other inflammatory non‐malignant diseases. New analysis tools enable deeper insight into the process of neutrophil differentiation and maturation. These technological and scientific developments led to the description of an ever‐increasing number of distinct transcriptional states and associated phenotypes in murine models of disease and more recently also in humans. At present, functional validation of these different transcriptional states and potential phenotypes in cancer is lacking. Current functional concepts on neutrophils in cancer rely mainly on the myeloid‐derived suppressor cell (MDSC) concept and the dichotomous and simple N1–N2 paradigm. In this manuscript, we review the historic development of those concepts, critically evaluate these concepts against the background of our own work and provide suggestions for a refinement of current concepts in order to facilitate the transition of TAN research from experimental insight to clinical translation.

Neutrophils and their friends

“…Segal et al 2 detail the reciprocal crosstalk in the TME that occurs among neutrophils, platelets, T‐lymphocytes, and malignant cells to sculpt the local environment and modulate tumor behavior. The N1 and N2 nomenclature surfaces again, as in the review by Antuamine et al 16 and once more the authors encourage caution in extrapolating neutrophil subtypes identified in murine systems to the human condition.…”

“…One of the challenges central to the discussion of TAN relates to myeloid‐derived suppressor cells and the characterization of neutrophils alternatively as tumor‐promoting (N2) or anti‐tumor (N1). Antuamine et al 16 discuss the history of these concepts and nomenclature and offer critical analyses of their merits and shortcomings.…”

“…It is clear that despite the relatively little amount of IL-1β released on a per cell basis, neutrophils serve as a major source of its production at inflammatory sites simply because of the abundance of neutrophils that accumulate. 16 and once more the authors encourage caution in extrapolating neutrophil subtypes identified in murine systems to the human condition.…”

NETosis: Sculpting tumor metastasis and immunotherapy

“…They function as a crucial immunosuppressive component in cancer‐bearing hosts. Myeloid‐derived suppressor cells are usually classified as two major subpopulations: mononuclear MDSCs (mMDSCs) and polymorphonuclear or granulocytic‐MDSCs (PMN‐MDSCs or gMDSCs) 146 . IL‐8 chemoattracts both human granulocytic and monocytic MDSCs 147 .…”

Stimuli‐responsive nanodelivery systems for amplifying immunogenic cell death in cancer immunotherapy

“…In synergy with PD‐L1 inhibitor, tumor cell membrane‐cloaked KP1339‐loaded mesoporous organosilica nanoparticles can suppress primary tumor growth with low systemic toxicity as well as alleviate distant spread and lung metastases. MDSCs are the major accomplices of tumor overgrowth and antitumor immunosuppression, 128 and can be recruited via tumor‐derived cytokines (e.g., granulocyte‐colony stimulating factor (G‐CSF) and granulocyte‐macrophage colony stimulating factor (GM‐CSF)) 129 . Abundant lactate dehydrogenase A (LDHA) during glycolysis is often accompanied by abundant tumor‐derived G‐CSF and GM‐CSF, subsequently facilitating the recruitment of MDSCs and immunosuppression 130 .…”