Synergistic effect of adoptive T-cell therapy and intratumoral interferon γ-inducible protein-10 transgene expression in treatment of established tumors
Synergistic effect of adoptive T-cell therapy and intratumoral interferon γ-inducible protein-10 transgene expression in treatment of established tumors
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DOI：
10.1016/s0008-8749(02)00508-7
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发表时间：
2002-05-01
影响因子：
4.3
通讯作者：
Xiang, J
中科院分区：
文献类型：
--
作者：
Huang, H;Liu, YQ;Xiang, J
缺乏有效的T细胞对肿瘤的渗透是成功采用T细胞治疗的主要障碍。我们以前已经证明，移植的表达淋巴肌动蛋白的SP2/0骨髓瘤总是由SP2/0肿瘤特异性T细胞介导的肿瘤退行性变。在这里，我们进一步系统地描述了这些激活的T细胞，并研究了它们的治疗效果，无论是单独使用趋化因子干扰素-伽马(干扰素-伽马)诱导蛋白-10(IP-10)基因治疗。经SP2/0细胞刺激后，这些活化的T细胞为CD2 5(+)FasL(+)L选择素(LOW)，表达CXCR3受体，并在体外被IP-10化学吸引。这两种细胞均表达干扰素-γ、穿孔素和肿瘤坏死因子-α，但不表达IL-4。活化的T细胞对SP2/0肿瘤细胞有很强的细胞毒作用(特异性杀伤率为79%；E.T比为50)，主要通过穿孔素途径。用标记的T细胞进行细胞跟踪证实，这些T细胞比不表达IP-10的肿瘤更好地渗透到IP-10表达的肿瘤中。在体内，联合瘤内IP-10基因转移和对已建立的SP2/0肿瘤的过继T细胞免疫治疗在8只小鼠中有7只肿瘤被根除，对照或IP-10腺病毒治疗本身既不改变荷瘤小鼠的致死结果，也不单独T细胞治疗，尽管后两种治疗方法确实推迟了其时间框架。综上所述，我们的数据提供了可靠的证据，表明过继T细胞治疗和IP-10基因转移到肿瘤组织中具有强大的协同作用，最终根除了成熟的肿瘤肿块。(C)2002年ELSE-VIER科学(美国)。版权所有。
The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have previously shown that transplanted SP2/0 myelorna tumors engineered to express lymphotactin invariably induced tumor regress mediated by SP2/0 tumor-specific T cells. Herein, we further systemically characterize these activated T cells and investigate their therapeutic efficacy, either alone or with the chemokine interferon gamma (IFN-gamma)-inducible protein-10 (IP-10) gene therapy. Following stimulation with SP2/0 cells, these activated T cells were CD25(+)FasL(+) L-selectin(low), expressed CXCR3 receptor and were chemoattracted by IP-10 in vitro. They comprised 64% CD4(+) Th1 and 36% CD8(+) Tcl cells, both of which expressed IFN-gamma, perforin, and TNF-alpha, but not IL-4. The activated T cells were strongly cytotoxic for SP2/0 tumor cells (79% specific killing; E.T ratio, 50), mainly via perforin-mediated pathway. Cell tracking using labeled T cells confirmed that these T cells infiltrated better into the IP-10-expressing tumors than non-IP-10-expressing ones. In vivo, combined intratumoral IP-10 gene transfer and adoptive T-cell immunotherapy for well-established SP2/0 tumors eradicated the tumors in 7 of the 8 mice, Control or IP-10 adenoviral treatments by themselves neither alter the lethal outcome for tumor-bearing mice nor did T-cell therapy by itself, although the latter two treatments did stow its time-frame. Taken together, our data provide solid evidence of a potent synergy between adoptive T-cell therapy and IP-10 gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses. (C) 2002 Else-vier Science (USA). All rights reserved.