Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
J Immunother Cancer. 2022 May;10(5). doi: 10.1136/jitc-2021-003960.
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.
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 细胞浸润到免疫荒漠肿瘤仍然是一个主要的限制因素。一种优化的疫苗方法来诱导能够进行强有力的肿瘤浸润的抗原特异性 T 细胞对于加速其临床转化非常重要。我们之前开发了一种 STING 激活的 PC7A 纳米疫苗，该疫苗在皮下注射时会产生强烈的抗肿瘤 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，研究了瘤内给药和皮下给药纳米疫苗对肿瘤生长的抑制作用。通过临床相机成像检测纳米疫苗在体内的分布，通过体内细胞毒性杀伤测定和流式细胞术检测全身 T 细胞激活和肿瘤浸润。为了进行机制分析，通过体内迁移阻断测定、多重趋化因子阵列、流式细胞术、RT-qPCR、趋化性测定和基因敲除小鼠研究了 T 细胞的募集。
研究发现，纳米疫苗的给药方式改变了肿瘤中 T 细胞的产生和浸润。与皮下给药相比，瘤内给药纳米疫苗在多种肿瘤模型中显示出更好的抗肿瘤效果。机制研究表明，与皮下注射相比，纳米疫苗瘤内给药显著增加了 TC-1 肿瘤中抗原特异性 T 细胞的浸润。纳米疫苗抑制肿瘤生长主要依赖于 CD8 细胞毒性 T 细胞。纳米疫苗在肿瘤中的积累以 STING 依赖的方式上调髓样细胞中的 CXCL9 表达，导致来自外周的 IFNγ表达的 CD8 T 细胞的募集增加，IFNγ反过来刺激髓样细胞中的 CXCL9 表达，导致髓样细胞-CXCL9 和 T 细胞-IFNγ 之间的正反馈，促进 T 细胞的募集。然而，在存在系统缺乏抗原特异性 T 细胞的情况下，单独的 STING 激动剂无法维持这种效应。
我们的结果表明，PC7A 纳米疫苗瘤内给药比皮下给药能产生更强的抗肿瘤免疫和疗效。这些数据表明，在纳米疫苗的临床应用中，瘤内给药应包括在治疗设计中。
