在临床前结直肠癌模型中,针对两种辐射诱导的免疫抑制途径提高常量分次放疗的疗效。

Jihane Boustani, Benoit Lecoester, Jérémy Baude, Charlène Latour, Emeric Limagne, Riad Ladjohoulou, Véronique Morgand, Lisa Froidurot, François Ghiringhelli, Gilles Truc, Olivier Adotévi, Céline Mirjolet
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引用次数: 0

摘要

目的:我们先前在小鼠结直肠癌模型中证实,常剂量 RT(normoRT:18 × 2 Gy)诱导 MDSC 浸润和 PD-L1 表达,而低剂量 RT(hypoRT:3 × 8 Gy)诱导 Treg。在此,我们想评估正常RT与针对两种辐射诱导的免疫抑制通路(MDSC和PD-L1)的治疗是否能改善肿瘤控制:用结肠肿瘤细胞(CT26)诱导免疫功能正常的小鼠(BALB/c)皮下肿瘤,并单独用RT(18×2 Gy或3×8 Gy)治疗,或同时用5-氟尿嘧啶(5FU)(10 mg/kg)和/或抗PD-L1(10 mg/kg)来消耗MDSC。我们通过流式细胞术评估了这些组合对肿瘤生长和免疫细胞浸润的影响。此外,我们还进行了肿瘤再挑战实验和 IFN-γ ELISpots,以研究长期记忆反应:结果:尽管与 5FU 组和未处理组相比,RT + 5FU 组的肿瘤生长明显延迟(p < .05),但 RT + 5FU 组(CRT)与单用 RT 组没有明显差异。正常RT结束1周后,MDSC的比例明显增加(8.09% ± 1.03%,p < .05),而加入5FU后,MDSC的比例下降(3.39% ± 0.69%,p < .05)。治疗后,表达 PD-L1 的肿瘤细胞增多。加入抗PD-L1可显著延缓肿瘤生长,获得最高的完全应答率,并诱导持久的保护性特异抗肿瘤免疫:这些结果表明了抑制两种辐射诱导的免疫抑制机制的意义。在患者中,常放疗联合 5FU 已经是局部晚期直肠癌的标准治疗方法。在这种治疗方法中加入抗PD-L1可能会取得很好的效果。
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Targeting two radiation-induced immunosuppressive pathways to improve the efficacy of normofractionated radiation therapy in a preclinical colorectal cancer model.

Purpose: We have previously demonstrated in a murine colorectal cancer model that normofractionated RT (normoRT: 18 × 2 Gy) induced MDSC infiltration and PD-L1 expression, while hypofractionated RT (hypoRT: 3 × 8 Gy) induced Treg. Here, we wanted to assess whether the association of normoRT with treatments that target two radiation-induced immunosuppressive pathways (MDSC and PD-L1) could improve tumor control.

Materials and methods: Subcutaneous tumors were induced using colon tumor cells (CT26) in immunocompetent mice (BALB/c) and were treated with RT alone (18 × 2 Gy or 3 × 8 Gy), or concomitantly with 5-Fluorouracil (5FU) (10 mg/kg) to deplete MDSC, and/or anti-PD-L1 (10 mg/kg). We assessed the impact of these combinations on tumor growth and immune cells infiltration by flow cytometry. In addition, we performed tumor rechallenge experiments and IFN-γ ELISpots to study the long-term memory response.

Results: Even though tumor growth was significantly delayed in the RT + 5FU compared to 5FU and untreated groups (p < .05), there was no significant difference between RT + 5FU (CRT) and RT alone. The rate of MDSC increased significantly 1 week after the end of normoRT (8.09% ± 1.03%, p < .05) and decreased with the addition of 5FU (3.39% ± 0.69%, p < .05). PD-L1 expressing tumor cells were increased after treatment. Adding anti-PD-L1 significantly delayed tumor growth, achieved the highest complete response rate, and induced a long-lasting protective specific anti-tumor immunity.

Conclusions: These results tend to demonstrate the interest of inhibiting two radiation-induced immunosuppressive mechanisms. In patients, the combination of normoRT with 5FU is already the standard of care in locally advanced rectal cancer. Adding an anti-PD-L1 to this treatment could show promising results.

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