Polarization of Tumor-Associated Neutrophil (TAN) Phenotype by TGF-β: “N1” versus “N2” TAN

By Z. Fridlender, Jing Sun, Samuel Kim, V. Kapoor, G. Cheng, L. Ling, G. Worthen, S. Albelda. Cancer Cell, 2009

3,164 citations recorded by the source corpus.

Summary TGF-β blockade significantly slows tumor growth through many mechanisms, including activation of CD8+ T-cells and macrophages. Here, we show that TGF-β blockade also increases neutrophil-attracting chemokines resulting in an influx of CD11b+/Ly6G+ tumor-associated neutrophils (TAN) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of pro-inflammatory cytokines. Accordingly, following TGF-β blockade, depletion of these neutrophils significantly blunts anti-tumor effects of treatment and reduces CD8+ T-cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8+ T-cells intra-tumorally. Together, these data suggest that TGF-β within the tumor microenvironment induces a population of TAN with a pro-tumor phenotype. TGF-β blockade results in the recruitment and activation of TAN with an anti-tumor phenotype.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/360fbf63fd939be00a40ae0f5bf0d3680f9a8c49

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Citations in the corpus

Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “In gastric cancer, TANs induce direct immunosuppression in T cells by PD-L1 expression induced by tumor-derived granulocyte macrophage-CSF (GM-CSF) (Wang et al. 2017).”
Tumor-associated neutrophils: new targets for cancer therapy. (2011, background): “In this study, inhibition of TGF-b in 2 different murine cancer models led to the generation of a unique population of "antitumor" neutrophils, which were hypersegmented, produced high levels of proinflammatory cytokines, and were cytotoxic to tumor cells (34).”
Myeloid-derived suppressor cells (2017, background): “Although the PMN-MDSCs concept is widely accepted, there are number of studies that use different approaches to the nomenclature of tumor-associated neutrophils (TAN), based on the concept of phenotypic plasticity of TANs, which is modulated through distinct micro-environmental signals, at different”
Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, background): “Indeed, tumors can manipulate neutrophils early in their differentiation process, creating a diverse repertoire of functional polarization states (Fridlender et al., 2009; Coffelt et al., 2016).”
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “It has been shown that in mice with depleted CD11b/Ly6G TANs had reduced tumor growth and increased activation of CD8 T cells (106).”
Diverse novel functions of neutrophils in immunity, inflammation, and beyond (2013, background): “Polarization of tumor-associated neutrophil phenotype by TGF-: “N1” versus “N2” TAN.”
Cancer-related inflammation: common themes and therapeutic opportunities. (2012, background): “Other inflammatory cells that have recently been identified as odifiers of some inflammatory tumor microenvironments are eutrophils [25–27] and mast cells, important not only for their elease of cytokines and chemokines but also reactive oxygen and roteases [2,28].”
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm (2010, background): “, and their N1-N2 polarization is reminiscent of macrophages in cance”