PDF(Pubmed)
Abstract：
BACKGROUND: Esophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC.
METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells.
RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast.
CONCLUSIONS: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.
METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells.
RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast.
CONCLUSIONS: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.
摘要：
背景：食管癌（EC）是一种全球性的溃疡，因其发病率居高不下而导致高死亡率，伴随着不屈不挠的复发和转移。然而,这些复杂的EC与NY-ESO-1抗原的过度表达有关，为过继性T细胞治疗提供了生命线。我们假设与NY-ESO-1结合的天然分离的高亲和力T细胞受体（TCR）将允许T淋巴细胞以明显的抗肿瘤反应功效靶向EC。此外，靶向TRPV2，它与EC的肿瘤发生有关，为双靶向治疗创造了一条途径。我们利用了针对EC的双重靶向抗肿瘤功效。
方法：我们从用富集的细胞毒性T淋巴细胞获得的TCR构建的幼稚文库中分离了抗原特异性TCR（asTCR）。我们的asTCR及其TCR-T细胞衍生物的鲁棒性，曲尼司特（TRPV2抑制剂），并使用前瞻性交叉反应性人肽变体和肿瘤细胞评估了其二价治疗。
结果：我们的研究表明，我们的幼稚未增强asTCR及其TCR-Ts延续了其同源HLA-A*02:01/NY-ESO-1（157-165）特异性，与靶向相同NY-ESO-1抗原的已知亲和力增强的TCR(TCRe)及其野生型(TCR0)相比,以更高的细胞毒性杀死不同的EC细胞。此外，与TCR-T或曲尼司特的任何单价处理相比，TCR-Ts和曲尼司特二价处理显示出优异的EC杀伤作用。
结论：我们的研究结果表明，双靶向免疫治疗可能具有更好的抗肿瘤作用。我们的研究提出了一种进化新颖的技术，健壮,对EC和其他恶性肿瘤的及时治疗策略和干预措施。
方法：我们从用富集的细胞毒性T淋巴细胞获得的TCR构建的幼稚文库中分离了抗原特异性TCR（asTCR）。我们的asTCR及其TCR-T细胞衍生物的鲁棒性，曲尼司特（TRPV2抑制剂），并使用前瞻性交叉反应性人肽变体和肿瘤细胞评估了其二价治疗。
结果：我们的研究表明，我们的幼稚未增强asTCR及其TCR-Ts延续了其同源HLA-A*02:01/NY-ESO-1（157-165）特异性，与靶向相同NY-ESO-1抗原的已知亲和力增强的TCR(TCRe)及其野生型(TCR0)相比,以更高的细胞毒性杀死不同的EC细胞。此外，与TCR-T或曲尼司特的任何单价处理相比，TCR-Ts和曲尼司特二价处理显示出优异的EC杀伤作用。
结论：我们的研究结果表明，双靶向免疫治疗可能具有更好的抗肿瘤作用。我们的研究提出了一种进化新颖的技术，健壮,对EC和其他恶性肿瘤的及时治疗策略和干预措施。
