Redirection to the bone marrow improves T cell persistence and antitumor functions.
Redirection to the bone marrow improves T cell persistence and antitumor functions.
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DOI：
10.1172/jci97454
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发表时间：
2018-05-01
期刊：
影响因子：
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通讯作者：
Chakraverty R
中科院分区：
文献类型：
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作者：
Khan AB;Carpenter B;Santos E Sousa P;Pospori C;Khorshed R;Griffin J;Velica P;Zech M;Ghorashian S;Forrest C;Thomas S;Gonzalez Anton S;Ahmadi M;Holler A;Flutter B;Ramirez-Ortiz Z;Means TK;Bennett CL;Stauss H;Morris E;Lo Celso C;Chakraverty R
基因修饰的T细胞治疗癌症成功的一个关键预测因素是转移细胞在患者体内的持久性。因此，分化程度较低的记忆T细胞有效扩增和存活的倾向使其成为临床应用的有吸引力的候选者。我们假设，将T细胞重定向到支持记忆分化的BM中的专门小生境将赋予增加的治疗功效。我们发现趋化因子受体CXCR 4在CD 8 + T细胞（TCXCR 4）中的过表达增强了它们向BM中血管相关CXCL 12+细胞的迁移，并增加了它们的局部植入。TCXCR 4进入BM微环境的增加诱导IL-15依赖性稳态扩增，并促进具有低表达程序性死亡-1、抗凋亡和产生多功能性精氨酸产生效应细胞的能力增强的记忆细胞样细胞的分化。转移到淋巴瘤荷瘤小鼠后，TCXCR 4显示出更大的效应子扩增能力和更好的肿瘤保护作用，后者独立于肿瘤床运输或调节性T细胞局部竞争的变化。因此，T细胞重定向归巢到BM赋予增加的记忆分化和抗肿瘤免疫，这表明了增加治疗性T细胞的持久性和功能的创新解决方案。
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15–dependent homeostatic expansion and promoted the differentiation of memory precursor–like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.