PO.CL08.02 · 临床研究
FLASH放疗改善小鼠胶质母细胞瘤的生存并保护循环中的抗原反应性CD8+ T细胞
FLASH radiotherapy improves survival in mouse glioblastoma and spares circulating antigen reactive CD8 + T-cells
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摘要 Abstract
中文摘要
引言：胶质母细胞瘤是一种致死性脑肿瘤，对目前包括手术、化疗和常规放疗（CONV-RT）在内的疗法反应不佳。尽管针对脑肿瘤的CONV-RT（0.01 Gy/秒）可刺激肿瘤抗原释放，但它也会募集免疫抑制性髓源性抑制细胞，并与神经毒性相关。超高剂量率或FLASH-RT在显著更短的时间内递送CONV-RT剂量（超过40 Gy/秒），在多种癌症类型中可维持肿瘤控制、减少正常组织损伤，且与CONV-RT相比免疫抑制性更低。在我们的研究中，我们比较了FLASH-RT与CONV-RT对同源GL261胶质母细胞瘤荷瘤小鼠的影响。我们假设FLASH-RT在肿瘤控制方面与CONV-RT效果相当或更优，并在肿瘤内和全身产生更少的免疫抑制。
方法：我们将2×10⁵个小鼠GL261细胞立体定向植入C57BL/6小鼠的右前脑。肿瘤起始5天后，对荷瘤小鼠进行假放疗（对照）、CONV-RT（平均剂量率>0.373 Gy/s）或FLASH-RT（平均剂量率>3.6×10⁶ Gy/s）处理。在治疗后第5天和第12天采集脑肿瘤组织和外周血。为评估CONV-RT或FLASH-RT后肿瘤微环境的变化，我们进行了10x Xenium空间转录组学分析（stRNA-seq；脑肿瘤，每组n=6只小鼠）、Lunaphore COMET多重免疫荧光检测（脑肿瘤，每组n=6只小鼠）和流式细胞术（外周单个核细胞，每组n=6只小鼠）。我们还评估了治疗后的生存结局（每组n=8只小鼠）。
结果：与CONV-RT（P<0.05）和假放疗（P<0.001）相比，FLASH-RT显著提高了GL261荷瘤小鼠的总生存率。与CONV-RT（P<0.01）和假放疗（P<0.01）相比，FLASH-RT治疗显著增加了肿瘤内CD8+ T细胞浸润。我们还发现，与FLASH-RT相比，CONV-RT导致循环中PD-1+CD8+ T细胞显著减少（P<0.01），该细胞群是一种强效的抗原反应性细胞毒性T细胞群，此前已在人类胶质母细胞瘤患者中被鉴定。
结论：FLASH-RT与小鼠GL261胶质母细胞瘤中更好的肿瘤控制、肿瘤内CD8+ T细胞浸润增加以及循环中抗原反应性PD1+CD8+ T细胞的保留相关。这些结果表明，FLASH-RT可能与免疫检查点抑制剂更好地协同，以重新激活针对胶质母细胞瘤的抗肿瘤T细胞反应。
查看英文原文 English abstract
Introduction: Glioblastoma is a lethal brain tumor with poor response to current therapies, which include surgery, chemotherapy, and conventional radiation therapy (CONV-RT). Although, CONV-RT (0.01Gy/second) to brain tumors stimulate tumor antigen release, it also recruits immunosuppressive myeloid-derived suppressor cells and is associated with neurotoxicity. Ultrahigh-dose-rate or FLASH-RT, which delivers CONV-RT doses over a significantly shorter period (more than 40Gy/second) maintains tumor control, reduces normal tissue injury and is less immunosuppressive compared to CONV-RT across multiple cancer types. In our study, we compared the effects of FLASH-RT to CONV RT in syngeneic mouse GL261 glioblastoma-bearing mice. We hypothesized that FLASH-RT would be equally or more effective than CONV-RT for tumor control and result in less immunosuppression within the tumor and systemically.
Methods: We stereotactically implanted 2 × 10 5 mouse GL261 cells into the right forebrain of C57BL/6 mice. Five days after tumor initiation, tumor bearing mice were treated with Sham-RT (control), CONV-RT (mean dose rate > 0.373 Gy/s), or FLASH-RT (mean dose rate >3.6x10 6 Gy/s). Brain tumor tissue and peripheral blood were collected on days 5 and 12 after treatment. To assess for changes in the tumor microenvironment after CONV-RT or FLASH-RT, we performed 10x Xenium spatial transcriptomics analysis (stRNA-seq; brain tumor, n = 6 mice per group), Lunaphore COMET multiplexed immunofluorescence assay (brain tumor, n = 6 mice per group), and flow cytometry (peripheral mononuclear cells, n = 6 mice per group). We also evaluated survival outcomes following treatment (n = 8 mice per group).
Results: FLASH-RT significantly improved overall survival rate of GL261 bearing mice compared to CONV-RT ( P <0.05 ) and Sham-RT ( P < 0.001 ). FLASH-RT treatment markedly increased intratumoral CD8+ T-cell infiltration compared with CONV-RT ( P <0.01 ) and Sham-RT ( P < 0.01 ). We also found that compared to FLASH-RT, CONV-RT caused a significant decrease in circulating PD-1 + CD8 + T-cells ( P < 0.01 ), a potent antigen reactive cytotoxic T-cell population previously identified in human patients with glioblastoma.
Conclusion: FLASH-RT is associated with better tumor control in mouse GL261 glioblastoma, increased intratumoral CD8+ T-cell infiltration, and preserves circulating antigen reactive PD1 + CD8 + T-cells. These results indicate that FLASH-RT may synergize better with immune checkpoint inhibitors to re-invigorate anti-tumor T-cell responses against glioblastoma.
利益披露 Disclosure
Y. Ma, None..
N. Nguyen, None..
X. Gui, None..
E. Aguilar, None..
L. Connell, None..
D. Neill, None..
E. Schüler, None..
C. I. Ene, None.