肿瘤细胞治疗研究
英文原题：Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
这些发现共同表明，senCAFs 具有强效促肿瘤作用，并提示通过衰老细胞清除疗法靶向 senCAFs 可能抑制乳腺癌的发生发展。
肿瘤微环境（TME）深刻影响肿瘤发生，乳腺 TME 中的基因表达可预测临床结局。TME 结构复杂，包含不同亚型的癌症相关成纤维细胞（CAF），但这些亚型对肿瘤发生的作用尚不明确。本研究在小鼠和人乳腺肿瘤中发现一类衰老的肌成纤维细胞 CAF（myCAF），称为 senCAF。利用 MMTV-PyMT;INK-ATTAC（INK）小鼠模型发现，senCAF 分泌的细胞外基质可特异性抑制自然杀伤（NK）细胞的细胞毒作用，从而促进肿瘤生长。通过遗传或药理方法清除 senCAF 可释放 NK 细胞杀伤能力并限制肿瘤生长。最后，研究显示 HER2 阳性、ER 阳性、三阴性乳腺癌及原位导管癌（DCIS）中均存在 senCAF，且其可预测肿瘤复发。综上，senCAF 强力促进肿瘤生长；靶向 senCAF 的衰老细胞清除疗法可能抑制乳腺癌发展。 意义：senCAF 限制 NK 细胞介导的杀伤，促进乳腺癌进展，因此靶向 senCAF 可能成为临床可行的抑制肿瘤进展策略。参见 Belle 等人发表于第 1324 页的相关论文。
The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.
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