Tumor-derived immunoglobulin like transcript 5 induces suppressive immunocyte infiltration in colorectal cancer.
Tumor-derived immunoglobulin like transcript 5 induces suppressive immunocyte infiltration in colorectal cancer.
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肿瘤源性免疫球蛋白样转录物 5 诱导结直肠癌中的抑制性免疫细胞浸润
作者：
免疫抑制细胞在肿瘤微环境（TME）中的浸润诱导结直肠癌（CRC）进展及其对免疫治疗的抵抗。鉴定调节抑制性免疫细胞浸润的肿瘤特异性因子将为CRC免疫治疗提供替代和新的靶点。免疫球蛋白样转录物（ILT）5是骨髓细胞活化的负调节因子。然而，其在实体瘤中的表达和功能作用仍然未知。利用人结直肠癌组织和细胞系，我们发现ILT5在结直肠癌细胞中的表达高于正常结直肠上皮细胞。肿瘤细胞中富集的ILT5与晚期肿瘤阶段和患者存活率低相关。我们随后的体外和体内研究表明，肿瘤来源的ILT5抑制T细胞的浸润，特别是TME中CD8+ T细胞的浸润，从而产生抑制性T细胞结构。此外，ILT5指导肿瘤相关巨噬细胞（TAM）的M2样极化。抑制肿瘤来源的ILT5恢复了免疫抑制性T细胞和TAM的结构，并限制了CRC的进展。我们的研究结果首次确定了ILT5在实体瘤细胞中的表达，并将ILT5作为CRC的潜在免疫靶点和预后预测因子。免疫球蛋白样转录物5（ILT5）在结直肠癌（CRC）细胞中富集，作为一种阴性预后生物标志物。CRC细胞中富集的ILT5抑制T细胞的浸润，特别是肿瘤微环境（TME）中的CD8+ T细胞的浸润，并指导肿瘤相关巨噬细胞的M2样极化。抑制肿瘤来源的ILT5恢复了免疫抑制性TME并限制了CRC进展。
Infiltration of immunosuppressive cells in the tumor microenvironment (TME) induced colorectal cancer (CRC) progression and its resistance to immunotherapy. Identification of tumor‐specific factors to modulate inhibitory immunocyte infiltration would provide alternative and novel targets for CRC immunotherapy. Immunoglobulin‐like transcript (ILT) 5 is a negative regulator of myeloid cell activation. However, its expression and functional role in solid tumors is still unknown. Using human CRC tissues and cell lines, we found that ILT5 was highly expressed in CRC cells compared with normal colorectal epithelial cells. Enriched ILT5 in tumor cells was correlated with advanced tumor stages and poor patient survival. Our subsequent in vitro and in vivo studies revealed that tumor‐derived ILT5 inhibited the infiltration of T cells, especially that of CD8+ T cells in the TME, creating suppressive T‐cell contexture. Furthermore, ILT5 directed M2‐like polarization of tumor‐associated macrophages (TAMs). Inhibition of tumor‐derived ILT5 restored the immunosuppressive T‐cell and TAM contexture, and restricted CRC progression. Our findings identified ILT5 expression in solid tumor cells for the first time and raised ILT5 as a potential immunotarget and prognostic predictor in CRC. Immunoglobulin‐like transcript 5 (ILT5) is enriched in colorectal cancer (CRC) cells, functioning as a negative prognostic biomarker. Enriched ILT5 in CRC cells inhibited the infiltration of T cells, especially that of CD8+ T cells in the tumor microenvironment (TME) and directed M2‐like polarization of tumor‐associated macrophages. Inhibition of tumor‐derived ILT5 restored the immunosuppressive TME and restricted CRC progression.
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DOI：
10.1186/s13058-016-0740-2
发表时间：
2016-08-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bussard KM;Mutkus L;Stumpf K;Gomez-Manzano C;Marini FC
通讯作者：
Marini FC
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
4.4
作者：
Martinez, Fernando O.;Gordon, Siamon;Mantovani, Alberto
通讯作者：
Mantovani, Alberto
影响因子：
2.8
作者：
Kruse, J.;von Bernstorff, W.;Partecke, L. I.
通讯作者：
Partecke, L. I.
影响因子：
12.4
作者：
Chen X;Gao A;Zhang F;Yang Z;Wang S;Fang Y;Li J;Wang J;Shi W;Wang L;Zheng Y;Sun Y
通讯作者：
Sun Y