Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy.
Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy.
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肿瘤内施用 STING 激活纳米疫苗可增强 T 细胞免疫治疗
DOI：
10.1136/jitc-2021-003960
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发表时间：
2022-05
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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癌症疫苗能够在早期临床试验中实现肿瘤特异性免疫编辑。然而，细胞毒性T细胞浸润到免疫遗弃的肿瘤中仍然是一个主要的限制因素。一种优化的疫苗方法来诱导抗原特异性T细胞，可以执行强大的肿瘤浸润是重要的，以加速其临床转化。我们之前开发了一种STING激活PC 7A纳米疫苗，该疫苗在皮下注射时产生强烈的抗肿瘤T细胞反应。本研究系统地研究了给药方法对纳米疫苗性能的影响。在TC-1人乳头瘤病毒诱导的癌症模型和B16-OVA黑色素瘤模型中研究了通过肿瘤内递送和皮下递送纳米疫苗的肿瘤生长抑制。通过临床摄像成像检测纳米疫苗在体内的分布，通过体内细胞毒性杀伤试验和流式细胞术检测全身T细胞活化和肿瘤浸润。对于机制分析，通过体内迁移阻断试验、多重趋化因子阵列、流式细胞术、RT-qPCR、趋化性试验和基因敲除小鼠研究T细胞募集。发现纳米疫苗施用改变肿瘤中的T细胞产生和浸润。与皮下递送相比，瘤内递送纳米疫苗在多种肿瘤模型中显示出上级抗肿瘤作用。机制研究表明，肿瘤内注射纳米疫苗显著增加了TC-1肿瘤中抗原特异性T细胞的浸润，尽管与皮下注射相比，T细胞的全身水平较低。纳米疫苗对肿瘤生长的抑制主要依赖于CD 8+细胞毒性T细胞。肿瘤中的纳米疫苗积累以STING依赖性方式上调髓样细胞中的CXCL 9表达，导致从外周募集表达IFNγ的CD 8 + T细胞增加，并且IFNγ γ刺激髓样细胞中的CXCL 9表达，导致髓样-CXCL 9和T细胞-IFN γ之间的正反馈以促进T细胞募集。然而，单独的STING激动剂在抗原特异性T细胞中存在全身性缺陷的情况下不能维持这种效果。我们的结果表明，肿瘤内施用PC 7A纳米疫苗比皮下注射获得更强的抗肿瘤免疫和功效。这些数据表明，肿瘤内给药应包括在纳米疫苗临床使用的治疗设计中。
Cancer vaccines are able to achieve tumor-specific immune editing in early-phase clinical trials. However, the infiltration of cytotoxic T cells into immune-deserted tumors is still a major limiting factor. An optimized vaccine approach to induce antigen-specific T cells that can perform robust tumor infiltration is important to accelerate their clinical translation. We previously developed a STING-activating PC7A nanovaccine that produces a strong anti-tumor T cell response on subcutaneous injection. This study systematically investigated the impact of administration methods on the performance of nanovaccines. Tumor growth inhibition by intratumoral delivery and subcutaneous delivery of nanovaccine was investigated in TC-1 human papillomavirus-induced cancer model and B16-OVA melanoma model. Nanovaccine distribution in vivo was detected by clinical camera imaging, systemic T cell activation and tumor infiltration were tested by in vivo cytotoxicity killing assay and flow cytometry. For mechanism analysis, T cell recruitment was investigated by in vivo migration blocking assay, multiplex chemokine array, flow cytometry, RT-qPCR, chemotaxis assay and gene knockout mice. Nanovaccine administration was found to alter T cell production and infiltration in tumors. Intratumoral delivery of nanovaccines displayed superior antitumor effects in multiple tumor models compared with subcutaneous delivery. Mechanistic investigation revealed that intratumoral administration of the nanovaccine significantly increased the infiltration of antigen-specific T cells in TC-1 tumors, despite the lower systemic levels of T cells compared with subcutaneous injection. The inhibition of tumor growth by nanovaccines is primarily dependent on CD8+ cytotoxic T cells. Nanovaccine accumulation in tumors upregulates CXCL9 expression in myeloid cells in a STING dependent manner, leading to increased recruitment of IFNγ-expressing CD8+ T cells from the periphery, and IFNγ reciprocally stimulates CXCL9 expression in myeloid cells, resulting in positive feedback between myeloid-CXCL9 and T cell-IFNγ to promote T cell recruitment. However, the STING agonist alone could not sustain this effect in the presence of a systemic deficiency in antigen-specific T cells. Our results demonstrate that intratumoral administration of PC7A nanovaccine achieved stronger antitumor immunity and efficacy over subcutaneous injection. These data suggest intratumoral administration should be included in the therapeutic design in the clinical use of nanovaccine.
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DOI：
10.1016/j.jconrel.2017.03.033
发表时间：
2017-10-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Luo M;Samandi LZ;Wang Z;Chen ZJ;Gao J
通讯作者：
Gao J
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
38.3
作者：
Luo M;Wang H;Wang Z;Cai H;Lu Z;Li Y;Du M;Huang G;Wang C;Chen X;Porembka MR;Lea J;Frankel AE;Fu YX;Chen ZJ;Gao J
通讯作者：
Gao J
DOI：
10.1038/s41577-019-0269-6
发表时间：
2020-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Irvine DJ;Dane EL
通讯作者：
Dane EL
影响因子：
82.9
作者：
通讯作者：
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