肿瘤细胞治疗研究
英文原题：Phospholipid scramblase 1 is involved in immunogenic cell death and contributes to dendritic cell-based vaccine efficiency to elicit antitumor immune response in vitro.
我们的结果表明，PLSCR1改善了由RA/IFN-α诱导的ICD相关钙网蛋白暴露，并且也明显参与了基于DC的疫苗效力，提示其可能在控制与DC激活相关的途径中发挥作用，可能包括那些参与抗原摄取及伴随的抗肿瘤免疫反应激活的途径。
从先前被能够促进免疫原性细胞死亡（ICD）的治疗杀死的癌细胞中获得的整个肿瘤细胞裂解物（TCLs），可以有效地用作肿瘤相关抗原的来源，用于开发高效的基于树突状细胞（DC）的疫苗。在此，研究了干扰素（IFN）诱导蛋白磷脂爬行酶1（PLSCR1）在影响濒死癌细胞的免疫原性特征以及增强基于DC的疫苗效率中的潜在作用。
在9-顺式维甲酸（RA）/IFN-α联合诱导ICD后，评估了不同套细胞淋巴瘤（MCL）细胞系中PLSCR1的表达，并使用商业激酶抑制剂来鉴定参与其上调的信号通路。构建了异位表达PLSCR1的Mino细胞系，以研究该蛋白在调节ICD特征中的潜在参与。从过表达PLSCR1的Mino细胞中获得的全TCL用于DC负载，负载后的DC用于生成肿瘤抗原特异性细胞毒性T淋巴细胞。
ICD诱导剂RA/IFN-α联合通过STAT1激活促进PLSCR1表达。PLSCR1上调有利于RA/IFN-α治疗的促凋亡效应，并增强钙网蛋白在细胞表面的暴露。此外，与负载空载体感染的Mino或亲本细胞系来源TCL的DCs相比，负载异位表达PLSCR1的Mino来源TCL的DCs在体外引发更强的T细胞介导的抗肿瘤反应。相反，PLSCR1敲低抑制了负载RA/IFN-α处理TCL的DCs引发cyclin D1肽特异性细胞毒性T淋巴细胞的刺激活性。
BACKGROUND AIMS: Whole tumor cell lysates (TCLs) obtained from cancer cells previously killed by treatments able to promote immunogenic cell death (ICD) can be efficiently used as a source of tumor-associated antigens for the development of highly efficient dendritic cell (DC)-based vaccines. Herein, the potential role of the interferon (IFN)-inducible protein phospholipid scramblase 1 (PLSCR1) in influencing immunogenic features of dying cancer cells and in enhancing DC-based vaccine efficiency was investigated. METHODS: PLSCR1 expression was evaluated in different mantle-cell lymphoma (MCL) cell lines following ICD induction by 9-cis-retinoic acid (RA)/IFN-α combination, and commercial kinase inhibitor was used to identify the signaling pathway involved in its upregulation. A Mino cell line ectopically expressing PLSCR1 was generated to investigate the potential involvement of this protein in modulating ICD features. Whole TCLs obtained from Mino overexpressing PLSCR1 were used for DC loading, and loaded DCs were employed for generation of tumor antigen-specific cytotoxic T lymphocytes. RESULTS: The ICD inducer RA/IFN-α combination promoted PLSCR1 expression through STAT1 activation. PLSCR1 upregulation favored pro-apoptotic effects of RA/IFN-α treatment and enhanced the exposure of calreticulin on cell surface. Moreover, DCs loaded with TCLs obtained from Mino ectopically expressing PLSCR1 elicited in vitro greater T-cell-mediated antitumor responses compared with DCs loaded with TCLs derived from Mino infected with empty vector or the parental cell line. Conversely, PLSCR1 knock-down inhibited the stimulating activity of DCs loaded with RA/IFN-α-treated TCLs to elicit cyclin D1 peptide-specific cytotoxic T lymphocytes. CONCLUSIONS: Our results indicate that PLSCR1 improved ICD-associated calreticulin exposure induced by RA/IFN-α and was clearly involved in DC-based vaccine efficiency as well, suggesting a potential contribution in the control of pathways associated to DC activation, possibly including those involved in antigen uptake and concomitant antitumor immune response activation.
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