The function and mechanism of mast cell in anti-colon cancer immunity 陈冠宇、凃康彦、衣欣、董凌云、李桂影、辛雪焕、孙航

CONTENTS The clinical manifestation of colon cancer 01 The clinical manifestation of colon cancer 02 A brief introduction involved in the anti-colon cancer immune microenvironment 03 The function and mechanism of mast cell involved in anti-colon cancer immunity

The symptoms of colon cancer LOREM 1、There may be no symptom in early stages. 2、After tumor ulceration, bleeding, toxin absorption, there often appears anemia, low - grade fever. 3、Cancer in late period can be characterized by abdominal distension and indigestion, and then some change in defecation habit, abdominal pain, or blood sticky mucus.

The microenvironment in anti-tumor immunity 1. cytokines exerting negative effect involved in the anti-colon cancer immunity 2. Cells involved in the anti-colon cancer

1. cytokines exerting negative effect involved in the anti-colon cancer immunity

(1) TNF-α-induced NF-κB activation TNF-α-induced NF-κB activation in myeloid cells is important for cancer development, and NF-κB activation in epithelial cells also contributes to tumor formation

(2) IL-6 induced the Stat3 activation The IL-6 cytokine family signals through a common receptor, gp130, which activates Stat3 which promotes tumor formation via which transforming growth factor (TGF)-β signaling promotes epithelial differentiation. P271

2. Cells involved in the anti-colon cancer (1) NK cell: Kills many types of tumor cells, especially cells reduced classⅠ MHC expression and can escape killing by CTL. (2) αβ T cells: αβ T cells contains the MHCⅠ restricted CD8+ CTL and MHCⅡ restricted with CD4+ Th cell. The activated CD4+ cells promote the activation of the CTL, and activate the MΦ in tumor immunity. After the activation of CTL, kill the tumor cells directly and kill the cytokines (IFN-γ) indirectly. (3) γδ T cells: Not restricted by MHC and kill cells that could escape from NK cells

P269 Macrophages take part in anti-tumor in different ways： Macropahges make great sense in anti-tumor immunity.Injection inside body of macrophages inhibitors such as anti-serum can promote the tumor growth;if we use the BCG or Corynebacterium parvum(短小棒状杆菌）to activate macrophages, the tumor growth can be inhibited and the tumor metastasis reducts.Pathological biopsy shows that the patient who has macrophage infiltration around the tumor has lower percentage of tumor metastasis and recovers better. Macrophages take part in anti-tumor in different ways： （1）Participate in the procession and presentation of tumor antigen，activate T cells and the specific immunity to kill the tumor cells. （2） Activated macrophages can release the oxidized metabolism products and lysosome enzymes （NO） to kill the tumor cells directly. （3）There is FcR in the surface of macrophage. The Fc mediates ADCC. （4）Activited macrophage can release TNF、IL-12 to kill the tumor cells or regulate the anti-tumor immunity. Macrophage that is activited has the ability of anti-tumor and has the selection which means it only kills the tumor cells not the normal cells. P269

(4) Dendritic cell DC has great ability of the presentation of Ag and it can promote the activitation and proliferation of T cells significantly to participate in the anti -tumor immunity. Some research shows that DC can inhibit the tumor cells directly .

The function and mechanism of mast cell in anti-colon cancer immunity

The function and mechanism of mast cell in anti-colon cancer immunity IL-33 LOREM TNF-α LOREM Allergen-Histamine LOREM MDSC LOREM

IL-33 (1)Attract more mast cell gathering. (2)IL-33 outside the nucleus bind specifically to ST2 on cell mambrane of mast cell and Th2 lymphocyte. (3)Intracellular IL-33 inhibits transcription factor NF-kB and reduces the expression of NF-kB-triggered proinflammatory genes. Dual function molecule : 1. Leading to the activation of intracellular signaling pathways similar to those used by IL-1,which related to Th2 immune response 2. IL-33 might be secreted via unconventional pathways, and can be released upon cell injury as an alarmin. .Th2免疫应答的效应：(如嗜酸性粒细胞与单核细胞浸润，粘液分泌增加，上皮细胞增生和肥大以及血清中嗜酸性粒细胞增多，血清IgA和IgE水平增高）

IL-33 involved in the migration of mast cells Day 0: MCs were distributed throughout the outer layers of the muscularis propria and serosa close to blood vessels. Day 0~Day 10：the MCs repositioned themselves from the outer to the inner intestinal layers, closer to the sites of mucosal regeneration. As colitis progressed, MCs moved into the tunica muscularis and the mucosa where they contacted the regenerating glands. Day 10~Day 17：MCs were enriched in the healed areas of the mucosa, and in close proximity to lymphoid aggregates within the LP.

The mast cell secrets TNF-α, which promotes the vicious proliferation

Histamine inhibits T cell proliferation OVA allergy acts on the mast cell which produces the histamine and releases it to act on Th0 cell. Releasing of histamine supports the normal innate allergic reactions and adoptive T helper cell activation, therefore regulates MC function through feedback manner, which maintains the homeostasis of the gut immunity.Histamine inhibits the Th0 cell to differentiate into Th1 cell and Th2 cell.

There are many different receptors of histamine on cells There are many different receptors of histamine on cells.The H2 receptor is one of the histamine's receptors expressing on the mast cells.When H2 receptor binds with histamine,it can cause a negative feedback reaction in type I hypersensitivity. Histamine can also binds with receptor which is expressed on T cells.It can stimulate T cell to produce adenylate cyclase.Then the level of cAMP increases,which can inhibit the proliferation of T cells and production of IL-2.

MC production of IL-17, leading to an expansion of MDSCs and suppression of CD8+ T cells.

MDSC Myeloid-derived suppressor cells is a kind of cells serving as the progenitor of DC, macrophage and granulocyte, which can contact with mast cell directly (via CD40-CD40L) and has a stronger function of suppresing immunity of CD8+ cell.

Under histamine deficiency, proinflammatory IL-17 produced by MCs augments MDSCs, in particular, upregulates Arg-1 and Cox-2 in MDSCs, thus promotes colorectal carcinogenesis.

Thus, it appears that the IL-17-expressing subset of MCs expanded in the setting of histamine deficiency is particularly effective in mobilizing and recruiting cancer-promoting MDSCs to the intestinal mucosa. OVA immunization of mice implanted with colon cancer cells led to significantly larger tumors with increased numbers of MCs and MDSCs. In the AOM/DSS colon carcinogenesis model, OVA immunization led to increased MCs and MDSCs, and increased colorectal tumors, which correlated with a reduction in CD8+ T cells.

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