Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses.
Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses.
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DOI：
10.1158/1078-0432.ccr-10-0712
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发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
Hwu P
中科院分区：
文献类型：
--
作者：
Peng W;Ye Y;Rabinovich BA;Liu C;Lou Y;Zhang M;Whittington M;Yang Y;Overwijk WW;Lizée G;Hwu P
在过继细胞转移(ACT)中最重要的限速步骤之一是T细胞向肿瘤的低效迁移。由于黑色素瘤特异性地表达趋化因子CXCL1和CXCL8，以促进单核细胞对CXCR2的依赖迁移，我们的目的是评估将CXCR2基因导入肿瘤特异性T细胞是否可以通过促进T细胞向肿瘤的迁移来进一步提高ACT的疗效。在本研究中，我们利用在H-2DB背景下识别gp100的转基因PMEL-1 T细胞，并将其转化为荧光素酶基因，以监测转移的T细胞在体内的迁移。为了显示肿瘤内表达荧光素酶的T细胞，非色素肿瘤是必需的。因此，我们利用了自然表达CXCL1的MC38肿瘤模型。与对照组相比，经CXCR2/荧光素酶转导的PMEL-1T细胞治疗的MC38/gp100肿瘤细胞小鼠的肿瘤消退和存活率显著提高。我们还利用生物发光成像观察到表达CXCR2的PMEL-1T细胞在这些小鼠的肿瘤部位优先聚集。将CXCR2转导的PMEL-1 T细胞转移到携带CXCL1转导B16肿瘤的小鼠体内，与对照组PMEL-1 T细胞治疗的小鼠相比，在肿瘤消退和存活方面观察到类似的增强。这些结果表明，将CXCR2基因导入肿瘤特异性T细胞可以增强其对肿瘤的定位，提高抗肿瘤免疫应答。这一策略可能最终实现基于肿瘤表达趋化因子的癌症治疗的个性化。
One of the most important rate-limiting steps in adoptive cell transfer (ACT) is the inefficient migration of T cells to tumors. Since melanomas specifically express the chemokines CXCL1 and CXCL8 that are known to facilitate the CXCR2-dependent migration by monocytes, our aim is to evaluate whether introduction of the CXCR2 gene into tumor-specific T cells could further improve the effectiveness of ACT, by enhancing T-cell migration to tumor. In this study, we utilized transgenic pmel-1 T cells which recognize gp100 in the context of H-2Db, that were transduced with luciferase gene to monitor the migration of transferred T cells in vivo. In order to visualize luciferase-expressing T cells within a tumor, a non-pigmented tumor is required. Therefore, we utilized the MC38 tumor model which naturally expresses CXCL1. Mice bearing MC38/gp100 tumor cells treated with CXCR2/luciferase-transduced pmel-1 T cells showed enhanced tumor regression and survival compared to mice receiving control luciferase transduced pmel-1 T cells. We also observed preferential accumulation of CXCR2-expressing pmel-1 T cells in the tumor sites of these mice using bioluminescence imaging. A similar enhancement in tumor regression and survival was observed when CXCR2-transduced pmel-1 T cells were transferred into mice bearing CXCL1-transduced B16 tumors compared to mice treated with control pmel-1 T cells. These results implicate that the introduction of the CXCR2 gene into tumor-specific T cells can enhance their localization to tumors and improve antitumor immune responses. This strategy may ultimately enable personalization of cancer therapies based on chemokine expression by tumors.