CXCL11型
癌症研究
溶瘤病毒
牛痘
趋化因子受体CCR5
CXCR3型
趋化因子
嵌合抗原受体
T细胞
CCL17型
趋化因子受体
医学
免疫学
生物
免疫系统
肿瘤细胞
基因
生物化学
重组DNA
作者
Edmund K. Moon,Liang-Chuan S. Wang,Kheng Bekdache,Rachel C. Lynn,Albert Lo,Stephen H. Thorne,Steven Μ. Albelda
出处
期刊:OncoImmunology
[Informa]
日期:2018-01-09
卷期号:7 (3): e1395997-e1395997
被引量:108
标识
DOI:10.1080/2162402x.2017.1395997
摘要
T cell trafficking into tumors depends on a “match” between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor “mismatch”, with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy.
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