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TIM-4 通过抑制 IL-6 分泌增加胰腺导管腺癌微环境中 CD4+CD25+FOXP3+调节性 T 细胞的比例。

TIM-4 increases the proportion of CD4CD25FOXP3 regulatory T cells in the pancreatic ductal adenocarcinoma microenvironment by inhibiting IL-6 secretion.

机构信息

Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.

Department of General Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China.

出版信息

Cancer Med. 2024 Sep;13(17):e70110. doi: 10.1002/cam4.70110.

DOI:10.1002/cam4.70110
PMID:39235042
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11375529/
Abstract

BACKGROUND

Currently, creating more effector T cells and augmenting their functions is a focal point in pancreatic ductal adenocarcinoma (PDAC) treatment research. T cell immunoglobulin domain and mucin domain molecule 4 (TIM-4), known for promoting cancer progression in various malignancies, is implicated in the suppressive immune microenvironment of tumors. Analyzing of the role of TIM-4 in the immune regulation of PDAC can offer novel insights for immune therapy.

METHODS

We analyzed the TIM-4 expression in tumor specimens from PDAC patients. Meanwhile, multiple fluorescent immunohistochemical staining was used to study the distribution characteristics of TIM-4, and through tissue microarrays, we explored its correlation with patient prognosis. The influence of TIM-4 overexpression on cell function was analyzed using RNA-seq. Flow cytometry and ELISA were used for verification. Finally, the relationship between TIM-4 and T lymphocytes was analyzed by tissue microarray, and the impacts of TIM-4 on T cell subsets were observed by cell coculture technology and a mouse pancreatic cancer in situ model.

RESULTS

In PDAC, TIM-4 is mainly expressed in tumor cells and negatively correlated with patient prognosis. TIM-4 influences the differentiation of Treg by inhibiting IL-6 secretion in pancreatic cancer cells and facilitates the proliferation of pancreatic cancer in mice. Additionally, the mechanism may be through the CD8 effector T cells (CD8Tc).

CONCLUSION

TIM-4 has the potential to be an immunotherapeutic target or to improve the efficacy of chemotherapy for PDAC.

摘要

背景

目前，增加效应 T 细胞数量并增强其功能是胰腺导管腺癌（PDAC）治疗研究的重点。T 细胞免疫球蛋白结构域和黏蛋白结构域分子 4（TIM-4）在多种恶性肿瘤中促进癌症进展，其与肿瘤抑制性免疫微环境有关。分析 TIM-4 在 PDAC 的免疫调节中的作用可为免疫治疗提供新的思路。

方法

我们分析了 PDAC 患者肿瘤标本中的 TIM-4 表达情况。同时，采用多荧光免疫组化染色研究 TIM-4 的分布特征，并通过组织微阵列探讨其与患者预后的相关性。通过 RNA-seq 分析 TIM-4 过表达对细胞功能的影响。采用流式细胞术和 ELISA 进行验证。最后，通过组织微阵列分析 TIM-4 与 T 淋巴细胞的关系，通过细胞共培养技术和小鼠胰腺原位模型观察 TIM-4 对 T 细胞亚群的影响。

结果

在 PDAC 中，TIM-4 主要在肿瘤细胞中表达，与患者预后呈负相关。TIM-4 通过抑制胰腺癌细胞中 IL-6 的分泌影响 Treg 的分化，并促进小鼠胰腺癌细胞的增殖。此外，其机制可能是通过 CD8 效应 T 细胞（CD8Tc）。

结论

TIM-4 有可能成为 PDAC 的免疫治疗靶点或提高化疗疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/d8e8a341eae2/CAM4-13-e70110-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/50e28b02e27e/CAM4-13-e70110-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/3fb83456b5b3/CAM4-13-e70110-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/a146d8cf926d/CAM4-13-e70110-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/97801caf496d/CAM4-13-e70110-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/d8e8a341eae2/CAM4-13-e70110-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/50e28b02e27e/CAM4-13-e70110-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/3eea16064e53/CAM4-13-e70110-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/ec5c87ccab01/CAM4-13-e70110-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/3fb83456b5b3/CAM4-13-e70110-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/a146d8cf926d/CAM4-13-e70110-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/97801caf496d/CAM4-13-e70110-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/069b/11375529/d8e8a341eae2/CAM4-13-e70110-g006.jpg

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本文引用的文献

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Function and characteristics of TIM‑4 in immune regulation and disease (Review).TIM-4 在免疫调节和疾病中的功能和特性（综述）。
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Tim-4 cavity-resident macrophages impair anti-tumor CD8 T cell immunity.Tim-4 腔室驻留巨噬细胞损害抗肿瘤 CD8 T 细胞免疫。
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