Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA; Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, PR China.
Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Exp Cell Res. 2018 Mar 1;364(1):113-123. doi: 10.1016/j.yexcr.2018.01.041. Epub 2018 Feb 1.
Previous reports, including our experimental results, showed that macrophages migrate to prostate cancer (PCa) cells. We tested whether the migrated macrophages affect the susceptibility of castration-resistant PCa (CRPC) cells to cytotoxic actions of natural killer (NK) cells. We found treatment of tumor cells with the conditioned media (CM) of the PMA/IL-4 treated THP-1 cells (M2 type macrophages) (THP-1 CM) decreased the susceptibility of tumor cells to NK cell cytotoxicity, as a result of increased programmed death receptor ligand 1 (PD-L1) and decreased NK group 2D (NKG2D) ligands in CRPC cells. Meanwhile, the decreased susceptibility of tumor cells was also detected when NK cells were treated with THP-1 CM and used in NK cell cytotoxicity tests. Therefore, we observed higher resistance of CRPC cells when both tumor and NK cells were treated with THP-1 CM than when tumor cells or NK cells were individually treated. We further discovered that the PMA/IL-4 treated THP-1 cells secrete a high level of IL-6, so blocking the IL-6 action significantly decreased the PD-L1 level while recovering the NKG2D ligands, thus increasing the susceptibility of CRPC cells to NK cell action. Moreover, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling in triggering the THP-1 CM effect. Consequently, we found the susceptibility of CRPC cells to NK cells was increased when either JAK or Stat 3 inhibitor was added when tumor cells were treated with THP-1 CM, and that the best effect was observed when the JAK inhibitor and PD-L1 Ab were added together.
先前的报告，包括我们的实验结果，表明巨噬细胞迁移到前列腺癌（PCa）细胞。我们测试了迁移的巨噬细胞是否会影响去势抵抗性前列腺癌（CRPC）细胞对自然杀伤（NK）细胞细胞毒性作用的敏感性。我们发现，用 PMA/IL-4 处理的 THP-1 细胞（M2 型巨噬细胞）的条件培养基（CM）（THP-1 CM）处理肿瘤细胞，会增加 CRPC 细胞中程序性死亡受体配体 1（PD-L1）并减少 NK 组 2D（NKG2D）配体，从而降低肿瘤细胞对 NK 细胞细胞毒性的敏感性。同时，当 NK 细胞用 THP-1 CM 处理并用在 NK 细胞细胞毒性试验中时，也检测到肿瘤细胞敏感性降低。因此，当肿瘤细胞和 NK 细胞均用 THP-1 CM 处理时，我们观察到 CRPC 细胞的抗性更高，而当肿瘤细胞或 NK 细胞单独处理时则没有这种情况。我们进一步发现，PMA/IL-4 处理的 THP-1 细胞会分泌高水平的 IL-6，因此阻断 IL-6 作用会显著降低 PD-L1 水平，同时恢复 NKG2D 配体，从而增加 CRPC 细胞对 NK 细胞作用的敏感性。此外，我们发现 JAK-Stat3 是触发 THP-1 CM 作用的 IL-6 下游信号转导中最关键的信号。因此，当肿瘤细胞用 THP-1 CM 处理时，添加 JAK 或 Stat 3 抑制剂会增加 CRPC 细胞对 NK 细胞的敏感性，当同时添加 JAK 抑制剂和 PD-L1 Ab 时效果最佳。
