调节性T细胞促进GATA-3阴性的ER阳性乳腺癌嗜骨转移机制的研究

Bone metastasis is an significant issue in the field of breast cancer research.Tumor stroma plays an important role in the process of cancer metastasis, however, the role of tumor stroma for tumor specificity organ metastasis is unclear. Recent studies have found that CD4+CD25-T cells were high expression in the stroma of ER positive breast cancer, while Treg was low expression. When Tregs were high expression, ER positive breast cancer would easy metastasis, GATA-3 expression in metastatic ER positive breast cancer was usually missing.Our preliminary study found that Tregs were high expression in the peripheral blood, bone marrow, and tumor tissue of ER positive breast cancer patients, suggesting that Tregs may promote GATA-3 negative ER positive breast cancer migrate to bone. In this project we will determine whether Treg in tumor stroma mainly from TGF-β-induced CD4 + CD25-T cells; Treg in stroma could increase the invasive of breast cancer by RANKL/RANK pathway; Treg in stroma migrate to bone marrow through CXCR4/CXCL12 pathway; Treg in the marrow formed immunosuppressive inhibited niches in the bone marrow and then promote breast cancer metastasize to bone specially. This study will clarify all aspects of Tregs in the process of breast cancer bone metastasis. Thus, our study might provide a novel strategy targeting Tregs to prevent and treat GATA-3 negative ER positive breast cancer bone metastasis.

ER阳性乳腺癌嗜骨转移是亟待解决的重要问题，肿瘤基质对肿瘤侵袭转移起重要作用，但对肿瘤特异性脏器转移的影响尚不清楚。研究证实，ER阳性乳腺癌基质中以CD4+CD25-T细胞为主，Treg比例低，当Treg 高表达时易发生转移，而转移的ER阳性乳腺癌通常GATA-3表达缺失。我们前期发现，ER阳性骨转移乳腺癌患者外周血、骨髓和肿瘤中Treg增加，推测Treg可能促进GATA-3阴性的ER阳性乳腺癌嗜骨转移。本项目拟通过实验在GATA-3阴性的ER阳性乳腺癌中证实，基质中Treg 来源于TGF-β诱导的CD4+CD25-T细胞转化，可通过RANKL/RANK增加乳腺癌转移性，基质中Treg通过CXCR4/CXCL12迁移到骨髓，在骨髓中形成免疫抑制龛境促进乳腺癌嗜骨转移。本研究将明确Treg在乳腺癌骨转移各个环节中的作用，为从Treg入手延缓GATA-3阴性的ER阳性乳腺癌骨转移提供理论依据。

ER阳性乳腺癌嗜骨转移是亟待解决的重要问题，肿瘤基质对肿瘤侵袭转移起重要作用，但对肿瘤特异性脏器转移的影响尚不清楚。研究证实，ER阳性乳腺癌基质中以CD4+CD25-T细胞为主，Treg比例低，当Treg 高表达时易发生转移，而转移的ER阳性乳腺癌通常GATA-3表达缺失。我们前期发现，ER阳性骨转移乳腺癌患者外周血、骨髓和肿瘤中Treg增加，推测Treg可能促进GATA-3阴性的ER阳性乳腺癌嗜骨转移。本项目通过实验在GATA-3阴性的ER阳性乳腺癌中证实，基质中Treg 来源于TGF-β诱导的CD4+CD25-T细胞转化，可通过RANKL/RANK增加乳腺癌转移性，基质中Treg通过CXCR4/CXCL12迁移到骨髓，在骨髓中形成免疫抑制龛境促进乳腺癌嗜骨转移。本研究明确了Treg在乳腺癌骨转移各个环节中的作用，还在临床研究中证实临床一线治疗前血浆sPD-L1水平可作为转移性乳腺癌良好的肿瘤标志物，也可用于监测患者治疗反应。