PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells
PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells
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DOI：
10.1093/intimm/dxh194
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发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Honjo, T
中科院分区：
文献类型：
--
作者：
Iwai, Y;Terawaki, S;Honjo, T
由于转移是癌症患者死亡的主要原因，因此迫切需要开发新的治疗方法来控制癌细胞的血行播散。之前，我们和其他人证明了一种新的机制，该机制允许肿瘤通过表达PD-L1来逃避宿主免疫应答，PD-L1可以通过与PD-1（一种属于CD 28家族的免疫抑制受体）的相互作用来负调节免疫应答。在这项研究中，我们报告了免疫原性差的B16黑色素瘤细胞向肝脏的血行播散在PD-1缺陷小鼠中受到抑制。接种于脾脏后，在体外不表达PD-L1的肿瘤细胞上诱导PD-L1。与野生型小鼠相比，向PD-1缺陷小鼠脾内注射B16细胞显示脾中效应T细胞的诱导增强，T细胞增殖和细胞因子产生延长，以及效应T细胞向肝脏中肿瘤部位的归巢增强，导致效应T细胞在肿瘤部位的积累。通过遗传操作或抗体处理的PD-1阻断不仅抑制了在C57 BL/6背景下B16黑色素瘤细胞向肝脏的血行播散，而且抑制了在BALB/c背景下CT 26结肠癌细胞向肺的播散。这些结果表明，PD-1阻断可能是治疗各种肿瘤细胞血行播散的有力工具。
Since metastasis is the major cause of death for cancer patients, there is an urgent need to develop new therapies to control hematogenous dissemination of cancer cells. Previously we and others demonstrated a novel mechanism that allows tumors to escape from the host immune response by expressing PD-L1 which can negatively regulate immune response through the interaction with PD-1, an immunoinhibitory receptor belonging to the CD28 family. In this study, we report that hematogenous spread of poorly immunogenic B16 melanoma cells to the liver was inhibited in PD-1-deficient mice. After inoculation to spleen, PD-L1 was induced on tumor cells, which did not express PD-L1 in vitro. As compared with wild-type mice, intrasplenic injection of B16 cells into PD-1-deficient mice showed enhanced induction of effector T cells in spleen, prolonged T cell proliferation and cytokine production, and augmented homing of effector T cells to tumor sites in the liver, resulting in accumulation of effector T cells in the tumor sites. PD-1 blockade by genetic manipulation or antibody treatment inhibited not only hematogenous dissemination of B16 melanoma cells to the liver on the C57BL/6 background, but also dissemination of CT26 colon cancer cells to the lung on the BALB/c background. These results suggest that PD-1 blockade may be a powerful tool for treatment of hematogenous spread of various tumor cells.