肿瘤细胞治疗研究
英文原题：Latent EBV reactivation drives aberrant B-cell proliferation during ex vivo tumor-infiltrating lymphocyte expansion from EBV-negative rectal cancer tumor tissue.
近期研究强调了CAR-T和TIL（肿瘤浸润淋巴细胞）治疗中疱疹病毒相关风险，尤其是HHV6和Epstein Barr病毒（EBV），部分原因是体外细胞操作。
近期研究强调了疱疹病毒相关风险，尤其是HHV6和Epstein Barr病毒（EBV），在CAR-T和TIL（肿瘤浸润淋巴细胞）疗法中的风险，部分原因是由于体外细胞操作。EBV驱动的B细胞过度生长可在TIL扩增过程中发生，而EBV转化的B细胞可能发挥免疫调节功能，可能影响TIL疗法的疗效和安全性，这些领域仍未得到充分探索。在此，我们表征了一株自发产生的野生型EBV转化B细胞系lcl_burn0214，该细胞系是在一名EBV阴性的直肠癌患者肿瘤标本的体外培养过程中建立的。lcl_burn0214细胞系已传代70次，并通过HLA基因分型、免疫表型分析（CD19、CD20）、B细胞受体克隆型分析确认为患者来源的单克隆B细胞系。RNA-seq分析显示，lcl_burn0214的基因表达与淋巴母细胞样细胞高度相似（r = 0.88），而非恶性B淋巴瘤。在免疫缺陷小鼠中，lcl_burn0214表现出有限的致瘤性。自体TILs为B细胞阴性，在与lcl_burn0214或EBV肽池共培养时，在ELISPOT试验中表现出强烈的干扰素-γ反应（每百万TILs 1000 1800个斑点）。我们的发现强调了在制造过程中监测TIL产品中EBV阳性B细胞污染的重要性，以确保即使对于EBV阴性患者也能保证安全性和治疗疗效。
Recent studies underscore herpesvirus-associated risks, especially HHV6 and Epstein Barr virus (EBV), in CAR-T and tumor-infiltrating lymphocyte (TIL) therapies, partly due to ex vivo cell manipulation. EBV-driven B cell outgrowth can occur during TIL expansion, and EBV-transformed B cells may exert immunomodulatory functions, potentially impacting TIL therapy efficacy and safety areas that remain underexplored. Here, we characterized a spontaneously arising wild-type EBV-transformed B cell line, lcl_burn0214, established during ex vivo culture of a tumor specimen from a rectal cancer patient who was EBV-negative. The lcl_burn0214 cell line has undergone 70 passages and was confirmed as a monoclonal B cell line of patient origin via HLA genotyping, immunophenotyping (CD19, CD20), B cell receptor clonotype analysis. RNA-seq analysis revealed that lcl_burn0214 s gene expression closely resembles that of lymphoblastoid cells (r = 0.88) rather than malignant B lymphomas. In immunocompromised mice, lcl_burn0214 exhibited limited tumorigenicity. Autologous TILs were negative for B cells and exhibited a strong interferon-gamma response in the ELISPOT assay during coculture with lcl_burn0214 or with the EBV peptide pool (1000 1800 spots per million of TILs). Our findings underscore the importance of monitoring TIL products for EBV-positive B cell contamination during manufacturing to ensure safety and therapeutic efficacy even for EBV-negative patients.
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