PO.CL05.13 · 临床研究
一种源自条件重编程原代肿瘤细胞的衰老全细胞疫苗平台,可启动强效T细胞免疫并在小鼠乳腺癌模型中克服ICI耐药
A senescent whole-cell vaccine platform derived from conditionally reprogrammed primary tumor cells primes potent T-cell immunity and overcomes ICI resistance in murine breast cancer models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景:包括乳腺癌在内的侵袭性癌症面临治疗耐药和复发的挑战。自体癌症疫苗因难以获得足够的原代肿瘤材料而受限。我们的实验室采用条件重编程细胞(CRC)方法实现原代肿瘤细胞的长期体外扩增。我们正在开发一种基于细胞衰老(一种高度免疫原性状态)的新型疫苗策略。我们假设,通过CRC生成的经辐照的衰老全肿瘤细胞(SWC)将作为强效的多抗原疫苗发挥作用,启动强健的抗肿瘤T细胞应答,与免疫检查点抑制剂(ICI)协同,并建立长期免疫记忆。
实验方法:通过gamma射线辐照在小鼠乳腺癌细胞系中诱导衰老。通过将SWC注射至初治的同基因小鼠来评估免疫启动作用,并通过流式细胞术定量脾脏和淋巴结中的全身性T细胞激活(CD4+、CD8+、CD69+、PD-1+)。将在原位荷瘤小鼠中评估治疗疗效,这些小鼠接受SWC疫苗+CpG佐剂治疗,联合或不联合双重ICI阻断(抗PD-L1/抗CTLA-4)。终点包括肿瘤消退和生存期。疫苗疗效还将在预防性和术后抗复发模型(模拟R1/R2残留病灶)中进行测试。
新数据摘要:体内免疫启动实验(每周四次注射)表明,衰老肿瘤细胞引发了强健的全身性适应性免疫应答。与对照相比,SWC治疗的小鼠在脾脏和淋巴结中显示出CD8alpha+和CD4+T细胞群体的显著扩增。流式细胞术揭示CD8+T细胞呈现激活的效应表型,CD69和细胞毒性标志物升高。这些发现证实SWC具有高度免疫原性并诱导全身性T细胞激活。
结论:通过CRC方法衍生的衰老全肿瘤细胞是一种可行且强效的多抗原疫苗平台。我们的初步数据表明,该策略打破了免疫耐受,诱导强健的T细胞激活。这为推进这种个性化自体疫苗以克服免疫耐药并预防侵袭性实体瘤复发提供了充分的理论依据。
查看英文原文 English abstract
Background: Aggressive cancers, including breast cancer, face challenges of therapeutic resistance and recurrence. Autologous cancer vaccines are limited by difficulties in obtaining sufficient primary tumor material. Our lab uses the Conditional Reprogramming Cell (CRC) method to enable long-term in vitro expansion of primary tumor cells. We are developing a novel vaccine strategy based on cellular senescence, a highly immunogenic state. We hypothesize that irradiated, senescent whole-tumor cells (SWCs) generated via CRC will function as potent, poly-antigenic vaccines to prime robust anti-tumor T-cell responses, synergize with immune checkpoint inhibitors (ICIs), and establish long-term immune memory.
Experimental method: Senescence was induced in murine breast cancer lines by gamma-irradiation. Immune priming was assessed by injecting SWCs into naïve syngeneic mice, quantifying systemic T-cell activation (CD4⁺, CD8⁺, CD69⁺, PD-1⁺) in spleens and lymph nodes via flow cytometry. Therapeutic efficacy will be evaluated in orthotopic, tumor-bearing mice treated with SWC vaccine + CpG adjuvant, +/- dual ICI blockade (anti-PD-L1/anti-CTLA-4). Endpoints include tumor regression and survival. Vaccine efficacy will also be tested in prophylactic and post-surgical anti-recurrence models (simulating R1/R2 residual disease).
Summary of new data: In vivo immune-priming experiments (four weekly injections) demonstrated that senescent tumor cells elicited a robust, systemic adaptive immune response. Compared to controls, SWC-treated mice showed a marked expansion of both CD8alpha⁺ and CD4⁺ T-cell populations in spleens and lymph nodes. Flow cytometry revealed an activated effector phenotype with elevated CD69 and cytotoxic markers in CD8⁺ T cells. These findings confirm SWCs are highly immunogenic and induce systemic T-cell activation.
Conclusion: Senescent whole-tumor cells derived via the CRC method are a feasible and potent poly-antigenic vaccine platform. Our preliminary data demonstrate that this strategy breaks immune tolerance, inducing robust T-cell activation. This provides a strong rationale for advancing this personalized, autologous vaccine to overcome immune resistance and prevent recurrence in aggressive solid tumors.
利益披露 Disclosure
S. Rasouli, None..
C. Cao, None..
W. Gong, None..
H. Li, None..
B. Liu, None..
A. Vilgelm, None..
J. Li, None..
X. Liu, None.