Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
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DOI：
10.1016/j.cell.2019.10.029
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发表时间：
2019-11-14
期刊：
影响因子：
64.5
通讯作者：
Sharma, Padmanee
中科院分区：
文献类型：
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作者：
Jiao, Shiping;Subudhi, Sumit K.;Sharma, Padmanee
免疫检查点疗法（ICT）在一部分转移性去势抵抗性前列腺癌（mCRPC）患者中显示出令人鼓舞的结果，但在骨转移患者中仍引发次优反应。对患者骨髓样本的分析显示，免疫检查点疗法后，辅助性T细胞17（Th17）亚群增加，而非辅助性T细胞1（Th1）亚群增加。为了进一步评估不同的肿瘤微环境，我们给小鼠皮下或骨内注射前列腺肿瘤细胞。在皮下CRPC模型中，免疫检查点疗法显著增加肿瘤内辅助性T细胞1亚群并提高生存率。然而，在骨CRPC模型中，尽管肿瘤内CD4 T细胞增加，但这些细胞极化为辅助性T细胞17而非辅助性T细胞1谱系，免疫检查点疗法未能引发抗肿瘤反应。从机制上讲，骨内肿瘤促进破骨细胞介导的骨吸收，释放转化生长因子 - β（TGF - β），其抑制辅助性T细胞1谱系的发育。阻断转化生长因子 - β并联合免疫检查点疗法可增加辅助性T细胞1亚群，促进CD8 T细胞的克隆扩增，随后使骨CRPC消退并提高生存率。
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 T(h)17 instead of T(h)1 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 T(h)1 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 T(h)17 rather than T(h)1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-8, which restrains T(h)1 lineage development. Blocking TGF-beta along with ICT increases T(h)1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.