Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response.
Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response.
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DOI：
10.1080/2162402x.2020.1814620
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发表时间：
2020-09-06
期刊：
影响因子：
7.2
通讯作者：
Uemura Y
中科院分区：
文献类型：
--
作者：
Mashima H;Zhang R;Kobayashi T;Hagiya Y;Tsukamoto H;Liu T;Iwama T;Yamamoto M;Lin C;Nakatsuka R;Mishima Y;Watanabe N;Yamada T;Senju S;Kaneko S;Idiris A;Nakatsura T;Ohdan H;Uemura Y
利用树突状细胞（DCs）进行免疫治疗是一种很有前途的癌症治疗方式。然而，来自外周血的功能性dc数量有限，这与目前基于dc的癌症免疫疗法的临床疗效不理想有关。我们之前通过基因工程诱导多能干细胞（iPSC-pMCs）衍生的骨髓细胞产生了增殖性抗原呈递细胞（APCs），这为癌症治疗提供了无限功能的APCs。在此，我们旨在通过基因改造进一步增强这些细胞的抗肿瘤作用。GM-CSF基因转移不影响原始iPSC-pMCs的形态或表面表型，但确实使iPSC-pMCs具有良好的生存能力。由此产生的细胞诱导了gm - csf依赖性CD8+ T细胞的稳态增殖，从而增强了抗原特异性T细胞的体外启动。给药的肿瘤抗原负载gm - csf产生iPSC-pMCs （GM-pMCs）有效地刺激抗原特异性T细胞和促进效应细胞浸润肿瘤组织，从而增强抗肿瘤作用。为了研究ipsc衍生产品的潜在致瘤性，研究人员发现辐照可以限制gm - pmc的增殖，同时保持其刺激T细胞的能力。此外，辐照细胞的抗肿瘤作用相当于从免疫功能小鼠获得的骨髓来源的dc。此外，与免疫检查点抑制剂联合使用可增加CD8+或NK1.1+效应细胞的浸润，减少CD11b+/Gr-1+细胞，但不会引起不良反应。因此，尽管gm - pmc具有与内源性dc不同的某些特征，但我们的研究结果表明，这些细胞可用于广泛的临床应用，并将提供质量一致的无限apc来源。
Immunotherapy using dendritic cells (DCs) is a promising treatment modality for cancer. However, the limited number of functional DCs from peripheral blood has been linked to the unsatisfactory clinical efficacies of current DC-based cancer immunotherapies. We previously generated proliferating antigen-presenting cells (APCs) by genetically engineering myeloid cells derived from induced pluripotent stem cells (iPSC-pMCs), which offer infinite functional APCs for broad applications in cancer therapy. Herein, we aimed to further enhance the antitumor effect of these cells by genetic modification. GM-CSF gene transfer did not affect the morphology, or surface phenotype of the original iPSC-pMCs, however, it did impart good viability to iPSC-pMCs. The resultant cells induced GM-CSF-dependent CD8+ T cell homeostatic proliferation, thereby enhancing antigen-specific T cell priming in vitro. Administration of the tumor antigen-loaded GM-CSF-producing iPSC-pMCs (GM-pMCs) efficiently stimulated antigen-specific T cells and promoted effector cell infiltration of the tumor tissues, leading to an augmented antitumor effect. To address the potential tumorigenicity of iPSC-derived products, irradiation was applied and found to restrict the proliferation of GM-pMCs, while retaining their T cell-stimulatory capacity. Furthermore, the irradiated cells exerted an antitumor effect equivalent to that of bone marrow-derived DCs obtained from immunocompetent mice. Additionally, combination with immune checkpoint inhibitors increased the infiltration of CD8+ or NK1.1+ effector cells and decreased CD11b+/Gr-1+ cells without causing adverse effects. Hence, although GM-pMCs have certain characteristics that differ from endogenous DCs, our findings suggest the applicability of these cells for broad clinical use and will provide an unlimited source of APCs with uniform quality.