In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models.
In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models.
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DOI：
10.1136/jitc-2021-002432
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发表时间：
2021-05
影响因子：
10.9
通讯作者：
Ito F
中科院分区：
文献类型：
--
作者：
Oba T;Makino K;Kajihara R;Yokoi T;Araki R;Abe M;Minderman H;Chang AE;Odunsi K;Ito F
树突状细胞 (DC) 具有启动抗原特异性 T 细胞并启动抗肿瘤免疫反应的能力，是癌症免疫治疗中很有前途的治疗靶点。基于 DC 的免疫治疗的一个主要障碍是难以获得足够数量的功能性 DC。理论上，使用诱导多能干细胞（iPSC）可以克服这一限制；然而，将 iPSC 衍生的 DC (iPSC-DC) 纳入癌症免疫治疗的治疗策略仍有待阐明。越来越多的证据表明，肿瘤驻留 DC 的诱导增强了放疗 (RT) 的免疫调节作用，促使我们研究 iPSC-DC 瘤内给药与局部放疗相结合的抗肿瘤功效。在粒细胞巨噬细胞集落刺激因子存在下，小鼠 iPSC 在表达缺口配体 delta-like 1 的 OP9 基质细胞上分化为 iPSC-DC。通过流式细胞术和成像流式细胞术评估 iPSC-DC 的表型和运输肿瘤引流淋巴结 (TdLN) 和初等抗原特异性 T 细胞的能力。在对抗 PD-1 配体 1 (PD-L1) 疗法耐药的同基因原位小鼠肿瘤模型中测试了瘤内注射 iPSC-DC 和 RT 的抗肿瘤功效。小鼠 iPSC-DC 在表型上与传统 2 型 DC 相似，并且在体外存在同源抗原的情况下能够促进抗原特异性 CD8+ T 细胞的激活、增殖和效应分化。原位给予 iPSC-DC 和 RT 的组合促进了肿瘤特异性 CD8+ T 细胞的启动，并协同延迟了治疗肿瘤和远处未照射肿瘤的生长。从机制上讲，RT 增强了瘤内注射的 iPSC-DC 向 TdLN 的运输，上调 CD40 表达，并增加 DC/CD8+ T 细胞聚集的频率。肿瘤浸润 CD8+ T 细胞和骨髓细胞的表型分析显示，肿瘤相关巨噬细胞和 DC 中干细胞样 Slamf6+ TIM3− CD8+ T 细胞和 PD-L1 表达增加。因此，联合治疗使免疫原性较差的肿瘤对抗 PD-L1 治疗产生反应，并形成肿瘤特异性免疫记忆。我们的研究结果说明了 iPSC-DC 的转化潜力，并确定了组合平台的治疗功效，使它们能够克服免疫原性差的肿瘤中对抗 PD-L1 疗法的耐药性。
Dendritic cells (DCs) are a promising therapeutic target in cancer immunotherapy given their ability to prime antigen-specific T cells, and initiate antitumor immune response. A major obstacle for DC-based immunotherapy is the difficulty to obtain a sufficient number of functional DCs. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSCs); however, therapeutic strategies to engage iPSC-derived DCs (iPSC-DCs) into cancer immunotherapy remain to be elucidated. Accumulating evidence showing that induction of tumor-residing DCs enhances immunomodulatory effect of radiotherapy (RT) prompted us to investigate antitumor efficacy of combining intratumoral administration of iPSC-DCs with local RT. Mouse iPSCs were differentiated to iPSC-DCs on OP9 stromal cells expressing the notch ligand delta-like 1 in the presence of granulocyte macrophage colony-stimulating factor. Phenotype and the capacities of iPSC-DCs to traffic tumor-draining lymph nodes (TdLNs) and prime antigen-specific T cells were evaluated by flow cytometry and imaging flow cytometry. Antitumor efficacy of intratumoral injection of iPSC-DCs and RT was tested in syngeneic orthotopic mouse tumor models resistant to anti-PD-1 ligand 1 (PD-L1) therapy. Mouse iPSC-DCs phenotypically resembled conventional type 2 DCs, and had a capacity to promote activation, proliferation and effector differentiation of antigen-specific CD8+ T cells in the presence of the cognate antigen in vitro. Combination of in situ administration of iPSC-DCs and RT facilitated the priming of tumor-specific CD8+ T cells, and synergistically delayed the growth of not only the treated tumor but also the distant non-irradiated tumors. Mechanistically, RT enhanced trafficking of intratumorally injected iPSC-DCs to the TdLN, upregulated CD40 expression, and increased the frequency of DC/CD8+ T cell aggregates. Phenotypic analysis of tumor-infiltrating CD8+ T cells and myeloid cells revealed an increase of stem-like Slamf6+ TIM3− CD8+ T cells and PD-L1 expression in tumor-associated macrophages and DCs. Consequently, combined therapy rendered poorly immunogenic tumors responsive to anti-PD-L1 therapy along with the development of tumor-specific immunological memory. Our findings illustrate the translational potential of iPSC-DCs, and identify the therapeutic efficacy of a combinatorial platform to engage them for overcoming resistance to anti-PD-L1 therapy in poorly immunogenic tumors.
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影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
6
作者：
Demirci S;Leonard A;Tisdale JF
通讯作者：
Tisdale JF
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G
影响因子：
15.3
作者：
Bonifaz, LC;Bonnyay, DP;Charalambous, A;Darguste, DI;Fujii, SI;Soares, H;Brimnes, MK;Moltedo, B;Moran, TM;Steinman, RM
通讯作者：
Steinman, RM