Laboratory of cellular immunology Neutrophils in cancer : Neutral no more title Laboratory of cellular immunology Lee Kyungmin

Contents Neutrophils origin and life cycle Neutrophils and tumor initiation Neutrophils and tumor growth Tumor metastasis Clinical implications contents

Immune cells and Neutrophils In humans, neutrophils are the most abundant immune cell population, representing 50–70% of all leukocytes. Immune cell population 50~70%

Granulopoiesis In tumour-bearing mice and humans with pancreatic or colon cancer (and probably other tumour types), the spleen is an alternative source of neutrophil production CFU-GM(granulocyte, macrophage) -adCre; control state +adCre; cancer state

Granulopoiesis Granulocyte-colony stimulating factor (G‑CSF) the master regulator of neutrophil generation and differentiation. acts at the level of myeloid progenitors to induce their proliferation and differentiation. Its receptor, G‑CSFR, is expressed throughout the myeloid lineage from early stem and progenitor cells to fully differentiated neutrophils, and G‑CSFR–signal transducer and activator of transcription 3 (STAT3) signalling governs neutrophil formation. G‑CSF is not absolutely required for granulopoiesis, as other molecules — such as granulocyte–macrophage-colony stimulating factor (GM‑CSF), interleukin 6 (IL‑6) and KIT ligand (KITL, also known as KITLG) — may have a redundant, but lesser, role22–24. Tumours in many mouse models of cancer upregulate these cytokines, causing overactive granulopoiesis and neutrophilia.

Neutrophil retention and release from bone marrow. Mature cells 1-2% only release from the bone marrow as terminally differentiated, mature cells Mature cells are retained in the bone marrow by an interplay between two C‑X‑C chemokine receptors, CXCR4 and CXCR2.

Many of the molecules that control neutrophil release from the bone marrow are frequently upregulated in tumors or systemically as a result of a tumor. These factors override retention signals in the bone marrow, facilitating neutrophil egress and elevated numbers of circulating neutrophils Cancer cells themselves produce these cytokines, but stromal and immune cells can also contribute to their elevated expression in tumour-bearing mice. (e.x. well-known source of IL‑1β)

Neutrophil lifespan  both macrophages and neutrophils in the tumor were retained longer than in the spleen (tumor, 48-96 hours; spleen, 24 hours), suggesting that the tumor microenvironment may not only recruit macrophages and neutrophils but also support their survival in situ The current paradigm is that circulating neutrophils have a half-life of approximately 7 hours in healthy humans, and 8–10 hours in mice. However, an equal number of reports challenge these kinetics as too short or too long. Neutrophils are also retained longer in tumors than in the spleen, suggesting that the tumor microenvironment encourages their survival both locally and systemically. the half-life of circulating neutrophils is extended in cancer patients to 17 hours, which may be the result of pro-survival signaling by G-CSF. A longer life may give neutrophils more time to synthesize new molecules and perform additional effector functions during tumor progression.

Neutrophils and tumour initiation

Neutrophils and tumour initiation Inflammation plays an essential part in initiating tumorigenesis by damaging specific tissues100, and neutrophils are a crucial component of this process. Inflammation-induced models of cancer initiated by chemical carcinogens, such as the DMBA–TPA skin cancer model and the azoxymethane (AOM)–dextran sodium sulfate (DSS) colitis-associated colon cancer model, have established the importance of neutrophils in tumour initiation. neutrophils can provide a causal link between inflammation and cancer.

How neutrophils foster tumorigenesis is not completely understood. Neutrophil-derived elastase and the immunosuppressive ability of neutrophils have both been implicated in tumour initiation, but the exact mechanisms need further elucidation. Neutrophil production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and angiogenic factors such as MMP9 may also be important for tumor initiation.

Neutrophils and tumor growth

Neutrophils and tumor growth

Tumor metastasis Metastasis is the spread of a cancer or other disease from one organ or part of the body to another without being directly connected with it. The new occurrences of disease thus generated are referred to as metastases. Neutrophils actively participate in various steps of the metastatic cascade: cancer cell escape from the primary tumor, intravasation into the blood and/or the lymphatic vascular system, survival in circulation, extravasation into distant organs and outgrowth of metastases

Tumour metastasis

Clinical implications Neutrophils as therapeutic targets in cancer patients

Clinical implications Combining neutrophil targeting with other anticancer therapies.  anti-Ly6G, when used in combination with anti–PD-1/anti–CTLA-4 antibodies, was effective.

Main reference Neutrophils in cancer: neutral no more Seth B. Coffelt, Max D. Wellenstein & Karin E. de Visser Nature Reviews Cancer 16, 431–446 (2016) doi:10.1038/nrc.2016.52Published online 10 June 2016

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