美国得克萨斯大学MD安德森癌症中心Padmanee Sharma课题组发现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疗法（ICT）的反应。该项研究成果发表在2019年11月14日出版的《细胞》上。

他们报道，尽管肿瘤内的CD4 T细胞极化了Th17而不是Th1谱系，但ICT无法在骨去势抵抗性前列腺癌（CRPC）模型中引发抗肿瘤反应。从机制上讲，骨骼中的肿瘤会促进破骨细胞介导的骨吸收，从而释放TGF-β，并抑制Th1谱系的发育。与ICT一起阻断TGF-β会增加Th1亚群并促进CD8 T细胞的克隆扩增以及随后骨CRPC的消退并提高生存率。

ICT在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效果，但在骨转移患者中效果仍不明显。对患者的骨髓样本进行分析后发现，用ICT治疗后，Th17增加，而不是Th1亚群增加。为了进一步评估不同的肿瘤微环境，他们向小鼠皮下或骨内注射了前列腺肿瘤细胞。皮下CRPC模型中的ICT显着增加了肿瘤内Th1亚群并提高了生存率。

附：英文原文

Title: Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

Author: Shiping Jiao, Sumit K. Subudhi, Ana Aparicio, Zhongqi Ge, Baoxiang Guan, Yuji Miura, Padmanee Sharma

Issue&Volume: 2019/11/14

Abstract: Immune checkpoint therapy (ICT) shows encouraging results in a subset of patientswith metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimalresponse among those with bone metastases. Analysis of patients’ bone marrow samplesrevealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, weinjected mice with prostate tumor cells either subcutaneously or intraosseously. ICTin the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor responsein the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, whichare polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorptionthat releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression ofbone CRPC and improves survival.

DOI: 10.1016/j.cell.2019.10.029

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31179-1