PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines.
PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines.
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DOI：
10.1158/0008-5472.can-12-1187
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发表时间：
2012-10-15
期刊：
影响因子：
11.2
通讯作者：
Hwu P
中科院分区：
文献类型：
--
作者：
Peng W;Liu C;Xu C;Lou Y;Chen J;Yang Y;Yagita H;Overwijk WW;Lizée G;Radvanyi L;Hwu P
连续性细胞转移（ACT）被认为是一种有前途的癌症治疗方式，但尽管正在进行的改进，许多患者没有经历临床获益。肿瘤微环境是免疫治疗中的一个重要限制因素，在ACT治疗中尚未完全解决。在这项研究中，我们报告了上调的免疫抑制受体PD-1表达的转移T细胞在肿瘤部位，在小鼠模型的ACT，与其表达的转移T细胞存在于外周血和脾脏。由于PD-1可以减弱T细胞介导的抗肿瘤应答，我们测试了用抗PD-1抗体阻断它是否可以增强ACT在该模型中的抗肿瘤活性。与单独使用任何一种药物的治疗相比，使用两种药物的共同治疗增加了肿瘤部位转移的T细胞数量，并增强了肿瘤消退。虽然抗PD-1没有减少荷瘤小鼠中存在的免疫抑制性Treg细胞和MDSC的数量，但我们发现它增加了肿瘤部位IFN-γ和CXCL 10的表达。使用IFN-γR-/-小鼠的骨髓移植实验表明IFN-γ是控制PD-1介导的T细胞肿瘤浸润的关键联系。综上所述，我们的结果表明阻断PD-1通路可以增加肿瘤部位的IFN-γ，从而增加免疫细胞进入恶性疾病部位的趋化因子依赖性运输。
Adoptive cell transfer (ACT) is considered a promising modality for cancer treatment, but despite ongoing improvements many patients do not experience clinical benefits. The tumor microenvironment is an important limiting factor in immunotherapy that has not been addressed fully in ACT treatments. In this study, we report that upregualtion of the immunosuppressive receptor PD-1 expressed on transferred T cells at the tumor site, in a murine model of ACT, compared with its expression on transferred T cells present in the peripheral blood and spleen. Since PD-1 can attenuate T cell-mediated antitumor responses, we tested whether its blockade with an anti-PD-1 antibody could enhance the antitumor activity of ACT in this model. Co-treatment with both agents increased the number of transferred T cells at the tumor site and also enhanced tumor regressions, compared to treatments with either agent alone. While anti-PD-1 did not reduce the number of immunosuppressive Treg cells and MDSCs present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site. Bone marrow transplant experiments using IFN-γR-/- mice implicated IFN-γ as a crucial nexus for controlling PD-1-mediated tumor infiltration by T cells. Taken together, our results imply that blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites.