Improved identification of tumor-specific TCRs from circulating lymphocytes using autologous colorectal tumor organoids

IF 10.1 1区 医学 Q1 ONCOLOGY
Lisha Ma , Xiya Wang , Qianjing Zhang , Zhaoya Gao , Xiangwen Ji , Zhilang Li , Yixian Li , Pengchong Zhang , Xuan Che , Yun Sun , Yun Bai , Hongkui Deng
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引用次数: 0

Abstract

The identification of effective T cell receptors (TCRs) with specific reactivity against tumor cells is critical for the efficacy of TCR-engineered T cell therapy. However, different approaches for screening effective TCRs remain to be explored. We developed an optimized approach to identify effective TCRs based on an organoid culture system with patient-derived tumor cells in the presence of oxaliplatin and autologous dendritic cells. By coculturing the immunogenic debris of patient tumor cells from the organoid, we successfully enriched tumor-reactive CD4+ and CD8+ T cells, enhanced the activation and proliferation of T cells, and could facilitate the identification of tumor-reactive CD8+ T cells from patients with MHC I-downregulated tumors. We further used autologous tumor organoids to verify that candidate tumor-specific TCRs can elicit patient-specific tumor recognition and killing when expressed in allogeneic T cells. Our organoid-based tumor-reactive T cell enrichment system and TCR screening validation platform provide an empirical strategy for the isolation of tumor-reactive T cells and can advance the study of TCR-engineered T cell therapy.
利用自体结直肠肿瘤类器官改进循环淋巴细胞中肿瘤特异性tcr的鉴定
鉴定对肿瘤细胞具有特异性反应性的有效T细胞受体(tcr)对于tcr工程T细胞治疗的有效性至关重要。然而,筛选有效tcr的不同方法仍有待探索。我们开发了一种优化的方法来鉴定有效的tcr,该方法基于奥沙利铂和自体树突状细胞存在的患者源性肿瘤细胞的类器官培养系统。通过共培养来自类器官的患者肿瘤细胞的免疫原性碎片,我们成功地富集了肿瘤反应性CD4+和CD8+ T细胞,增强了T细胞的活化和增殖,并且可以促进MHC i下调肿瘤患者的肿瘤反应性CD8+ T细胞的鉴定。我们进一步使用自体肿瘤类器官来验证候选肿瘤特异性tcr在异体T细胞中表达时可以引起患者特异性肿瘤识别和杀伤。我们基于类器官的肿瘤反应性T细胞富集系统和TCR筛选验证平台为肿瘤反应性T细胞的分离提供了一种经验策略,可以推进TCR工程T细胞治疗的研究。
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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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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