Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Dev Cell. 2023 Dec 4;58(23):2700-2717.e12. doi: 10.1016/j.devcel.2023.10.010. Epub 2023 Nov 13.
How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8 T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.
去分化的干细胞样肿瘤细胞如何逃避免疫监视仍知之甚少。我们发现，在去分化的肿瘤细胞中上调的谱系可塑性调节因子 SOX9 限制了鼠基底样乳腺癌癌前病变中浸润性 T 淋巴细胞的数量。SOX9 介导的免疫抑制是原位肿瘤进展为浸润性癌所必需的。SOX9 通过 STAT3 激活和直接转录调控诱导免疫检查点 B7x/B7-H4 的表达。B7x 在去分化的肿瘤细胞中上调，并保护它们免受免疫监视。B7x 还可保护免疫活性小鼠的乳腺再生。在晚期肿瘤中，B7x 靶向抑制肿瘤生长并克服对抗 PD-L1 免疫治疗的耐药性。在人乳腺癌中，SOX9 和 B7x 的表达呈正相关，并与 CD8 T 细胞浸润减少相关。本研究使用小鼠模型、细胞系和患者样本，确定了一种与去分化相关的免疫抑制机制，并证明了靶向 SOX9-B7x 通路在基底样乳腺癌中的治疗潜力。
