Despite its potency, the wider use of immunotherapy for B cell malignancies is hampered by the lack of well-defined tumor-specific Ags. In this study, we demonstrate that an evolutionarily conserved 37-kDa immature laminin receptor protein (OFA-iLRP), a nonimmunogenic embryonic Ag expressed by a variety of tumors, is rendered immunogenic if targeted to the APCs using the CCR6 ligands MIP3alpha/CCL20 and mDF2beta. The CCR6 targeting facilitated efficient Ag cross-presentation and induction of tumor-neutralizing CTLs. Although the Ag targeting alone, without activation of dendritic cells (DCs), is proposed to induce tolerance, and MIP3alpha does not directly activate DCs, the MIP3alpha-based vaccine efficiently induced protective and therapeutic antitumor responses. The responses were as strong as those elicited by the OFA-iLRP fusions with moieties that activated DCs and Th1-type cytokine responses, mDF2beta, or mycobacterial Hsp70 Ag. Although the same cDNA encodes the dimerized high-affinity mature 67-kDa mLRP that is expressed in normal tissues to stabilize the binding of laminin to cell surface integrins, the vaccines expressing OFA-iLRP elicited long-term protective CD8(+) T cell-mediated memory responses against syngeneic B cell lymphoma, indicating the potential application of these simple vaccines as preventive and therapeutic formulations for human use.

译文

:尽管缺乏效力,但缺乏明确的肿瘤特异性Ags阻碍了B细胞恶性肿瘤免疫治疗的广泛应用。在这项研究中,我们证明,如果使用CCR6配体MIP3alpha / CCL20和APC靶向APC,则进化上保守的37 kDa不成熟层粘连蛋白受体蛋白(OFA-iLRP)(一种由多种肿瘤表达的非免疫原性胚胎Ag)具有免疫原性。 mDF2beta。 CCR6靶向促进了有效的Ag交叉呈递和肿瘤中和性CTL的诱导。尽管有人提出仅将Ag靶向而不激活树突状细胞(DCs)来诱导耐受性,并且MIP3alpha不能直接激活DCs,但是基于MIP3alpha的疫苗有效地诱导了保护性和治疗性抗肿瘤反应。响应与由激活DC和Th1型细胞因子响应,mDF2beta或分枝杆菌Hsp70 Ag的部分的OFA-iLRP融合引发的响应一样强。尽管相同的cDNA编码在正常组织中表达的二聚化高亲和力成熟67-kDa mLRP,以稳定层粘连蛋白与细胞表面整联蛋白的结合,但表达OFA-iLRP的疫苗引起了CD8()T细胞介导的长期保护作用对同源B细胞淋巴瘤的记忆反应,表明这些简单疫苗作为人类预防和治疗制剂的潜在应用。

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