Zheng Guoxing, Liu Shanrong, Wang Peijie, Xu Ying, Chen Aoshuang
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL 61107, USA.
Cancer Res. 2006 Jul 1;66(13):6793-9. doi: 10.1158/0008-5472.CAN-06-0435.
T cells ectopically expressing costimulators are pathogenic and contribute to autoimmunity against self-antigens. Given that tumor antigens are often self-antigen or mutated self-antigens, we hypothesize that neoexpressing a costimulator on tumor-reactive T cells may likewise enhance their reactivity to tumor. To test this hypothesis, we have expressed B7-1 on OT-1 CD8+ T-cell receptor transgenic T cells via protein transfer (or protein "painting"). Naïve OT-1 T cells, after being painted with B7-1, can self-costimulate themselves, elicit enhanced proliferative and CTL responses to E.G7-ovalbumin tumor cells (expressing a cognate antigen), and become resistant to CD4+CD25+ regulatory T-cell-mediated suppression. Importantly, these T cells, when coimplanted with E.G7-ovalbumin tumor cells into a syngeneic host, are three to nine times more potent than are control T cells (mock painted with human IgG) in inhibiting tumor growth. Further, on transfer into mice bearing established E.G7-ovalbumin tumors, B7-1-painted ex vivo-amplified OT-1 T cells induced complete tumor regression in 65% of treated mice, whereas the control T cells did so in only 28% of treated mice. Finally, on transfer into mice bearing less immunogenic 4T1 breast tumors, B7-1-painted tumor-reactive CD8+ T cells improved the survival of treated mice to a greater extent than did the control T cells. Hence, this study establishes that arming tumor-reactive T cells with a costimulator can enhance their antitumor efficacy.
异位表达共刺激分子的T细胞具有致病性，并会导致针对自身抗原的自身免疫。鉴于肿瘤抗原通常是自身抗原或突变的自身抗原，我们推测在肿瘤反应性T细胞上新表达共刺激分子可能同样会增强它们对肿瘤的反应性。为了验证这一假设，我们通过蛋白质转移（或蛋白质“涂抹”）在OT-1 CD8⁺ T细胞受体转基因T细胞上表达了B7-1。用B7-1涂抹后的初始OT-1 T细胞能够自我共刺激，引发对E.G7-卵白蛋白肿瘤细胞（表达同源抗原）增强的增殖和CTL反应，并对CD4⁺CD25⁺调节性T细胞介导的抑制产生抗性。重要的是，当将这些T细胞与E.G7-卵白蛋白肿瘤细胞共同植入同基因宿主中时，它们在抑制肿瘤生长方面比对照T细胞（用人IgG模拟涂抹）有效三到九倍。此外，将体外扩增的经B7-1涂抹的OT-1 T细胞转移到已建立E.G7-卵白蛋白肿瘤的小鼠体内后，65%的处理小鼠中诱导了肿瘤完全消退，而对照T细胞在处理小鼠中仅为28%。最后，将经B7-1涂抹的肿瘤反应性CD8⁺ T细胞转移到免疫原性较低的4T1乳腺肿瘤小鼠体内后，与对照T细胞相比，更大程度地提高了处理小鼠的存活率。因此，本研究证实用共刺激分子武装肿瘤反应性T细胞可增强其抗肿瘤功效。
