通过CD8α的共表达增强tcr工程CD4 + T细胞的疗效。

IF 3.2 4区 医学 Q3 IMMUNOLOGY Journal of Immunotherapy Pub Date : 2023-05-01 DOI:10.1097/CJI.0000000000000456
Victoria E Anderson, Sara S Brilha, Anika M Weber, Annette Pachnio, Guy E Wiedermann, Sumaya Dauleh, Tina Ahmed, George R Pope, Laura L Quinn, Roslin Y Docta, Adriano Quattrini, Siobhan Masters, Neil Cartwright, Preetha Viswanathan, Luca Melchiori, Louise V Rice, Alexandra Sevko, Claire Gueguen, Manoj Saini, Barbara Tavano, Rachel J M Abbott, Jonathan D Silk, Bruno Laugel, Joseph P Sanderson, Andrew B Gerry
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引用次数: 1

摘要

用表达亲和增强T细胞受体(TCRs)的T细胞进行过继细胞治疗是一种很有前途的治疗实体瘤的方法。目前正在努力进一步设计这些T细胞,以增加临床反应的深度和持久性,并将疗效扩大到其他适应症。在本研究中,我们研究了一种这样的方法:用慢病毒载体转导T细胞,与CD8α辅助受体一起共表达针对MAGE-A4的亲和力增强的HLA i类限制性TCR。我们假设这种方法可以增强CD4 + t细胞辅助和效应功能,可能导致更有效的抗肿瘤反应。通过检测与黑色素瘤相关抗原A4 +肿瘤细胞培养的CD4 + T细胞和树突状细胞表面CD40配体表达和细胞因子和趋化因子分泌,检测转导CD4 + T细胞的活化情况。此外,还测量了t细胞对三维肿瘤球体的细胞毒活性。我们的数据表明,共表达TCR和CD8α共受体的CD4 + T细胞表现出增强的应答,包括CD40配体表达、干扰素分泌和细胞毒性活性,以及改善的树突状细胞活化。因此,我们的研究支持在HLA - i类限制性tcr工程T细胞中添加CD8α辅助受体以增强CD4 + T细胞功能,这可能潜在地提高患者抗肿瘤反应的深度和持久性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Enhancing Efficacy of TCR-engineered CD4 + T Cells Via Coexpression of CD8α.

Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In the present study, we investigated one such approach: T cells were transduced with a lentiviral vector to coexpress an affinity-enhanced HLA class I-restricted TCR directed against MAGE-A4 alongside a CD8α coreceptor. We hypothesized that this approach would enhance CD4 + T-cell helper and effector functions, possibly leading to a more potent antitumor response. Activation of transduced CD4 + T cells was measured by detecting CD40 ligand expression on the surface and cytokine and chemokine secretion from CD4 + T cells and dendritic cells cultured with melanoma-associated antigen A4 + tumor cells. In addition, T-cell cytotoxic activity against 3-dimensional tumor spheroids was measured. Our data demonstrated that CD4 + T cells coexpressing the TCR and CD8α coreceptor displayed enhanced responses, including CD40 ligand expression, interferon-gamma secretion, and cytotoxic activity, along with improved dendritic cell activation. Therefore, our study supports the addition of the CD8α coreceptor to HLA class I-restricted TCR-engineered T cells to enhance CD4 + T-cell functions, which may potentially improve the depth and durability of antitumor responses in patients.

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来源期刊
Journal of Immunotherapy
Journal of Immunotherapy 医学-免疫学
CiteScore
6.90
自引率
0.00%
发文量
79
审稿时长
6-12 weeks
期刊介绍: Journal of Immunotherapy features rapid publication of articles on immunomodulators, lymphokines, antibodies, cells, and cell products in cancer biology and therapy. Laboratory and preclinical studies, as well as investigative clinical reports, are presented. The journal emphasizes basic mechanisms and methods for the rapid transfer of technology from the laboratory to the clinic. JIT contains full-length articles, review articles, and short communications.
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