肿瘤细胞治疗研究
英文原题：E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer.
E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer.
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浸润性小叶乳腺癌（ILC）表现出特定的间质特征，且高 TIL（肿瘤浸润淋巴细胞）含量与患者预后不良相关。
浸润性小叶乳腺癌（ILC）具有特定的基质特征，且TIL（肿瘤浸润淋巴细胞）含量高与患者预后不良相关。本研究通过单细胞分析、免疫组化、大型女性 ILC 队列的 bulk RNA 测序去卷积分析及功能实验，揭示其潜在机制。研究显示，乳腺癌细胞中 E-钙黏蛋白（CDH1）缺失会阻碍 FAP⁺炎性癌相关成纤维细胞（iCAF）分化为 FAP⁺肌成纤维细胞样 CAF，导致 iCAF 在 ILC 中积聚。继而，FAP⁺ iCAF 将 TIL 招募至肿瘤中心，塑造其空间分布。随后，CDH1 失活的 ILC 癌细胞因不能滞留和激活表达 ITGAE 的组织驻留记忆 CD8⁺ T 淋巴细胞（TRM），而促进免疫逃逸。因此，本研究揭示了 CDH1 失活癌细胞、FAP⁺ iCAF 和 CD8⁺ TRM 之间的相互作用，增进了对 ILC 基质反应的理解，并解释了 ILC 患者中 TIL 为何以及如何与不良预后相关；这一机制可能推广至其他 CDH1 失活癌症类型。
Invasive lobular breast carcinoma (ILC) shows specific stromal features, and a high tumor-infiltrating lymphocyte (TIL) content being associated with poor patient prognosis. Here, we reveal the underlying mechanism by performing single-cell analysis, immunohistochemistry, deconvolution of bulk RNA-sequencing in a large female ILC series and functional assays. We show that E-cadherin (CDH1)-loss in breast cancer cells prevents differentiation of FAP+ inflammatory cancer-associated fibroblasts (iCAF) into FAP+ myofibroblastic CAF, leading to iCAF accumulation in ILC. In turn, FAP+ iCAF attract TILs into the tumor center, shaping their spatial organization. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape through a lack of retention and activation of ITGAE-expressing resident memory CD8 + T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, FAP+ iCAF and CD8 + TRM, providing insights into the ILC stromal reaction and revealing why and how TILs are associated with poor prognosis in ILC patients, a mechanism generalizable to other CDH1-inactivated cancer types.
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