CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：An autologous cell-based therapeutic vaccine expressing IL6/1 fusokine drives robust anti-tumor response against ovarian cancer.
An autologous cell-based therapeutic vaccine expressing IL6/1 fusokine drives robust anti-tumor response against ovarian cancer.
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这些发现表明，IL6/1 融合因子增强 T 细胞存活和增殖，同时促进记忆反应。表达 mIL6/1 融合因子的工程化癌细胞（ID8-F3）在卵巢癌小鼠模型中作为治疗性疫苗递送时，诱导了强烈的抗肿瘤反应。
细胞因子是免疫调节蛋白，在调控免疫反应中发挥核心作用，是癌症治疗中极具吸引力的靶点。然而，作为单一药物，细胞因子由于全身毒性及体内半衰期短，临床获益有限。我们课题组致力于工程化融合细胞因子（fusokines），即将两种细胞因子偶联为单一生物制剂，通过强制非经典受体结合与信号传导来重编程免疫细胞反应。我们构建了一种嵌合 IL-6/IL-1β 融合细胞因子，以验证以下假说：强制共结合 IL-6 和 IL-1β 信号通路将赋予 T 细胞功能获得性表型并促进强效抗肿瘤免疫。在此，我们描述了 IL6/1 融合细胞因子的免疫调节特性，以及一种在临床前小鼠模型中递送该融合细胞因子以抑制卵巢肿瘤生长的方法。
使用Vector Builder设计了编码鼠源或人源IL6/1的慢病毒载体，并根据后续实验需求分别在HEK293、CHO或ID8-F3（p53 -/-）细胞中表达。通过ELISA和流式细胞术验证了IL6/1的表达。通过流式细胞术监测人IL6/1（hIL6/1）对T细胞功能（增殖、记忆表型、活化诱导的凋亡）的影响。在体内研究中，将表达鼠源IL6/1（mIL6/1）的ID8-F3鼠源卵巢癌细胞通过腹腔注射（I.P.）作为细胞疗法给予携带已建立ID8-F3荧光素酶肿瘤的C57BL/6雌性小鼠。通过生物发光（BLI）成像监测肿瘤进展，并评估总生存期。
hIL6/1显著增强了T细胞存活，并选择性促进了CD45RO+记忆T细胞的活化和扩增。表达mIL6/1的ID8-F3细胞（ID8IL6/1）表现出稳定的转导和持续的细胞因子分泌。在体内，与对照组相比，ID8IL6/1细胞治疗显著减少了肿瘤生长并改善了总生存期，其中8只小鼠中有2只实现了肿瘤完全清除。
Cytokines are immunomodulatory proteins that play central roles in regulating immune responses and represent attractive targets for cancer therapy. However, as single agents, cytokines have shown limited clinical benefit due to systemic toxicities and a short in vivo half-life. Our group has focused on engineering fusion cytokines (fusokines) that couple two cytokines into a single biologic to reprogram immune cell responses by enforcing non-canonical receptor engagement and signaling. A chimeric IL-6/IL-1β fusokine was engineered to test the hypothesis that enforced co-engagement of IL-6 and IL-1β signaling pathways would confer a gain-of-function phenotype in T cells and promote robust anti-tumor immunity. Here, we describe the immunomodulatory properties of IL6/1 fusokine and a method to deliver this fusokine to produce inhibition of ovarian tumor growth in a pre-clinical mouse model.
Lentiviral vectors encoding murine or human IL6/1 were designed using Vector Builder and expressed in either HEK293, CHO or ID8-F3 (p53 -/- ) cells depending on the downstream experiment to be conducted. IL6/1 expression was validated by ELISA and flow cytometry. Effects of human IL6/1 (hIL6/1) on T cell function (proliferation, memory phenotype, activation induced apoptosis) were monitored by flow cytometry. For in vivo studies, ID8-F3 murine ovarian cancer cells expressing mouse IL6/1 (mIL6/1) were administered intraperitoneally (I.P.) as a cell-based therapy to C57BL/6 female mice bearing established ID8-F3 luciferase tumors. Tumor progression was monitored by bioluminescence (BLI) imaging, and overall survival was evaluated.
hIL6/1 significantly enhanced T cell survival and selectively promoted activation and expansion of CD45RO + memory T cells. mIL6/1 expressing ID8-F3 cells (ID8IL6/1) demonstrated stable transduction and sustained cytokine secretion. In vivo, ID8IL6/1 cell therapy significantly reduced tumor growth and improved overall survival compared to control groups, with 2 of 8 mice achieving complete tumor clearance.
These findings indicate that IL6/1 fusokine enhances T cell survival and proliferation while promoting memory responses. Engineered cancer cells (ID8-F3) expressing mIL6/1 fusokine induced a strong anti-tumor response when delivered as a therapeutic vaccine in ovarian cancer mouse model.
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