Mast Cell-Dependent CD8(+) T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in Apc(Min/+) Mice.
Mast Cell-Dependent CD8(+) T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in Apc(Min/+) Mice.
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DOI：
10.1158/2326-6066.cir-17-0424
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发表时间：
2018-03
影响因子：
10.1
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中科院分区：
文献类型：
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肥大细胞在某些人结直肠癌中的存在是一个积极的预后因素，但这种关联的基础还不完全清楚。在这里，我们发现在腺瘤性结肠息肉病基因（ApcMin/+）中具有杂合突变的小鼠显示出减少的肠道肿瘤负荷和增加的存活率，在趋化因子诱饵受体，ACKR 2-null背景下，这导致发现肥大细胞在肿瘤防御中的关键作用。ACKR 2 −/− ApcMin/+肿瘤显示肥大细胞浸润增加，在肥大细胞缺陷的ACKR 2 −/− SA−/− ApcMin/+小鼠中，随着肿瘤快速生长，它们的生存优势丧失，并且肥大细胞的过继转移恢复了对肿瘤生长的控制。来自ACKR 2 −/−小鼠的肥大细胞显示出升高的CCR 2和CCR 5表达，并且在抗原呈递和CD 8 + T细胞活化中也是有效的。肥大细胞衍生的白三烯B4（LTB 4）被发现是CD 8 + T淋巴细胞募集所必需的，因为缺乏LTB 4受体（ACKR 2 −/− BLT 1 −/− ApcMin/+）的小鼠对肠道肿瘤诱导的死亡高度敏感。总之，这些数据表明，趋化因子介导的肥大细胞的募集对于启动LTB 4/BLT 1调节的CD 8 + T细胞归巢和产生针对肠道肿瘤的有效抗肿瘤免疫是必不可少的。我们推测，这里报道的途径是肥大细胞在选定的人类肿瘤中的积极预后意义的基础。
The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (ApcMin/+) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2−/− ApcMin/+ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell–deficient ACKR2−/− SA−/− ApcMin/+ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2−/− mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8+ T cells. Mast cell–derived leukotriene B4 (LTB4) was found to be required for CD8+ T lymphocyte recruitment, as mice lacking the LTB4 receptor (ACKR2−/− BLT1−/− ApcMin/+) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB4/BLT1-regulated CD8+ T-cell homing and generation of effective antitumor immunity against intestinal tumors. We speculate that the pathway reported here underlies the positive prognostic significance of mast cells in selected human tumors.