PO.TB10.17 · 肿瘤生物学
高精度碳离子放疗引发有效的原位肿瘤疫苗接种和持久的抗肿瘤免疫
High-precision carbon ion radiotherapy elicits effective in-situ tumor vaccination and durable antitumor immunity
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摘要 Abstract
中文摘要
随着碳离子放疗（CIRT）的出现，外照射放疗的时空精度已几乎达到物理极限。我们试图研究 CIRT 在重编程肿瘤免疫微环境（TIME）方面的潜力。为此，系统研究了三种同基因肿瘤模型对分次（5 x 3 Gy）CIRT 与标准光子照射（XIRT）的反应。这些模型包括结直肠癌（MC-38）和前列腺癌（RM1）的典型 C57BL/6 肿瘤模型，以及基因工程非小细胞肺癌模型（Pik3ca+、p53+/−、Y856）。我们在所有三种模型中均观察到 CIRT 相比 XIRT 显著增强的抗肿瘤活性和相对生物学效应（RBE）。有趣的是，CIRT 在 MC-38 模型中实现了 100% 的治愈率，在 Y856 模型中为 67%，并在 RM1 模型中使中位总生存（OS）相比 XIRT 提高了三倍。免疫组织学、单细胞转录组及 CyTOF 分析显示，与对照相比，CIRT 治疗的肿瘤中免疫细胞浸润增强。此外，通过 MRI 追踪到 CIRT 后静脉转移的超顺磁性氧化铁纳米颗粒（SPION）标记 T 细胞的浸润增强。使用抗 CD8a 抗体清除细胞毒性 T 细胞以消除适应性免疫应答，可在所有三种肿瘤模型中显著减弱 CIRT 引发的抗肿瘤应答。在免疫缺陷的无胸腺裸鼠（Foxn1nu/nu）中的额外实验证实了适应性免疫在 CIRT 引发的抗肿瘤效应中的显著影响，表现为所有三种模型中 OS 明显降低且治愈率为零。为检验 CIRT 诱导的原位肿瘤疫苗接种的持久性，在 CIRT 后第 77 天于远隔（abscopal）部位对治愈小鼠进行再攻击。在 MC-38 模型中，100% 的远隔肿瘤在植入后 14 天内被排斥，表明 CIRT 诱导了强健而持久的全身抗肿瘤免疫。总之，我们的发现突显了适应性免疫对有效的 CIRT 诱导的 TIME 重编程以实现治愈性治疗的关键贡献。CIRT 可能提供一种新颖而有效的高精度时空可控的原位肿瘤疫苗接种手段。
查看英文原文 English abstract
With advent of carbon ion radiotherapy (CIRT) the spatio-temporal precision of external-beam radiotherapy has nearly reached the physical limits. We sought to investigate the potential of CIRT in reprograming the tumor immune microenvironment (TIME). To this end, three syngeneic tumor models were systematically investigated for their response to fractionated (5 x 3 Gy) CIRT vs. standard photon irradiation (XIRT). The models included the paradigmatic C57BL/6 tumor models of colorectal carcinoma (MC-38) and prostate cancer (RM1) as well as genetically engineered non-small cell lung cancer model (Pik3ca+, p53+/−, Y856). We observed substantially augmented antitumoral activity and relative biological effectiveness (RBE) of CIRT vs. XIRT in all three models. Intriguingly, CIRT achieved 100% cure rates in MC-38 and 67% in the Y856 model and increased the median overall survival (OS) three-fold vs. XIRT in the RM1 model. Immunohistological, single-cell transcriptome, and CyTOF analyses revealed enhanced immune cell infiltration in CIRT-treated tumors compared to controls. Moreover, enhanced infiltration of intravenously transferred Superparamagnetic Iron Oxide Nanoparticle (SPION) labelled T cells after CIRT was traced by MRI. The antitumoral responses elicited by CIRT could be significantly reduced in all three tumor models by abrogating the adaptive immune response via depletion of cytotoxic T cells using anti-CD8a antibodies. Additional experiments in immunocompromised athymic nude mice (Foxn1nu/nu) confirmed the significant impact of adaptive immunity in CIRT-elicited antitumoral effects with marked reduction of OS and zero cure rates across all three models. To examine the durability of CIRT-induced in-situ tumor vaccination, cured mice were rechallenged on abscopal sites at day 77 post-CIRT. In the MC-38 model, 100% of the abscopal tumors were rejected within 14 days after implantation indicating that CIRT induces a robust and durable systemic antitumor immunity. Together, our findings highlight the pivotal contribution of adaptive immunity to effective CIRT-induced TIME reprogramming for curative treatments. CIRT may provide novel and effective means of high-precision spatio-temporally controlled in-situ tumor vaccination.
利益披露 Disclosure
S. Meister, None..
M. Recusani, None..
M. Knoll, None..
R. Sinn, None..
A. Gahlawat, None..
J. Furkel, None..
M. Breckwoldt, None..
D. Jäger, None..
J. Debus, None..
A. Abdollahi, None.