肿瘤微环境的差异决定了辅助性 T 细胞谱系的极化和对免疫检查点治疗的反应。
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy.
机构信息
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth, Houston, TX 77030, USA.
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Cell. 2019 Nov 14;179(5):1177-1190.e13. doi: 10.1016/j.cell.2019.10.029.
Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased T17 instead of T1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral T1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to T17 rather than T1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains T1 lineage development. Blocking TGF-β along with ICT increases T1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
免疫检查点疗法（ICT）在转移性去势抵抗性前列腺癌（mCRPC）的一部分患者中显示出令人鼓舞的结果，但在有骨转移的患者中仍引发亚最佳反应。对患者骨髓样本的分析显示，ICT 后 T17 而不是 T1 亚群增加。为了进一步评估不同的肿瘤微环境，我们将前列腺肿瘤细胞皮下或骨内注射到小鼠体内。在皮下 CRPC 模型中，ICT 显著增加了肿瘤内 T1 亚群并改善了生存。然而，尽管肿瘤内 CD4 T 细胞增加，ICT 在骨 CRPC 模型中未能引发抗肿瘤反应，这些细胞被极化到 T17 而不是 T1 谱系。从机制上讲，骨中的肿瘤促进破骨细胞介导的骨吸收，释放 TGF-β，从而抑制 T1 谱系的发育。与 ICT 一起阻断 TGF-β可增加 T1 亚群，并促进 CD8 T 细胞的克隆扩增，随后骨 CRPC 消退并改善生存。
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