Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China.
National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China.
Sci Adv. 2020 Jan 29;6(5):eaax4690. doi: 10.1126/sciadv.aax4690. eCollection 2020 Jan.
CCR9 T cells have an increased potential to be activated and therefore may mediate strong antitumor responses. Here, we found, however, that CCL25, the only chemokine for CCR9 cells, is not expressed in human or murine triple-negative breast cancers (TNBCs), raising a hypothesis that intratumoral delivery of CCL25 may enhance antitumor immunotherapy in TNBCs. We first determined whether this approach can enhance CD47-targeted immunotherapy using a tumor acidity-responsive nanoparticle delivery system (NP-siCD47/CCL25) to sequentially release CCL25 protein and CD47 small interfering RNA in tumor. NP-siCD47/CCL25 significantly increased infiltration of CCR9CD8 T cells and down-regulated CD47 expression in tumor, resulting in inhibition of tumor growth and metastasis through a T cell-dependent immunity. Furthermore, the antitumor effect of NP-siCD47/CCL25 was synergistically enhanced when used in combination with programmed cell death protein-1/programmed death ligand-1 blockades. This study offers a strategy to enhance immunotherapy by promoting CCR9CD8 T cell tumor infiltration.
CCR9 T 细胞具有更强的激活潜力，因此可能介导强烈的抗肿瘤反应。然而，我们发现，CCR9 细胞唯一的趋化因子 CCL25 在人或鼠三阴性乳腺癌（TNBC）中并不表达，这提出了一个假设，即肿瘤内递送 CCL25 可能增强 TNBC 的抗肿瘤免疫治疗。我们首先确定了这种方法是否可以通过使用肿瘤酸度响应性纳米颗粒递药系统（NP-siCD47/CCL25）来增强针对 CD47 的免疫治疗，该系统可顺序释放 CCL25 蛋白和 CD47 小干扰 RNA 进入肿瘤。NP-siCD47/CCL25 显著增加了 CCR9CD8 T 细胞的浸润，并下调了肿瘤中的 CD47 表达，从而通过 T 细胞依赖性免疫抑制肿瘤生长和转移。此外，当与程序性细胞死亡蛋白 1/程序性死亡配体 1 阻断联合使用时，NP-siCD47/CCL25 的抗肿瘤作用得到协同增强。本研究提供了一种通过促进 CCR9CD8 T 细胞肿瘤浸润来增强免疫治疗的策略。
