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Advances in Synergistic Antitumor Effects of Radiopharmaceuticals Combined with Immune Checkpoint Inhibitors
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摘要: 靶向放射性核素治疗诱导DNA双链断裂，激活cGAS-STING通路、NF-κB/IRF3通路和STAT1/3-IRF1通路，上调程序性死亡受体配体1(programmed death-ligand 1，PD-L1)的表达，促炎细胞因子、CD8+ T细胞及CD4+ T细胞在肿瘤中浸润增加，为免疫检查点抑制剂治疗提供了有利的免疫原性微环境。联合治疗使得正向调节免疫反应的记忆效应T细胞、M1型巨噬细胞及树突状细胞浸润增加，免疫抑制性的调节性T细胞、M2型巨噬细胞及髓源性抑制细胞下调，部分小鼠肿瘤完全缓解并产生免疫记忆。值得注意的是，放射性诊断药物2-[18F]FDG联合PD-L1抗体治疗也可调控免疫微环境，显著提高疗效。本文主要综述目前典型的放射性药物联合免疫检查点抑制剂协同抗肿瘤治疗策略，并强调联合治疗时间窗以及不同的治疗组合可能改善治疗效果，提出诊断放射性药物联合免疫治疗有望成为一种新的肿瘤治疗范式，或将成为未来研究的重要方向。
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关键词:
- 2-[18F]FDG /
- 靶向放射性核素治疗 /
- PD-L1抗体 /
- 肿瘤免疫微环境
Abstract: Targeted radionuclide therapy (TRT) provides an immunogenic microenvironment for immune checkpoint inhibitor (ICI) therapy by inducing DNA double-strand break, activating the cGAS-STING, NF-κB/IRF3 and STAT1/3-IRF1 pathways, up-regulating the expression of PD-L1, and increasing the infiltration of pro-inflammatory cytokines, CD8+ T cells and CD4+ T cells in tumors. The combined therapy could increase the infiltration of memory effector T cells, M1 macrophages and dendritic cells which positively regulate immune response, and downregulate immunosuppressive regulatory T cells, M2 macrophages and myeloid-derived suppressor cells. Partial complete remission and immune memory were achieved in tumor-bearing mice treated with combined therapy. It is worth noting that radiodiagnostic agent 2-[18F]FDG combined with anti-PD-L1 mAb could also reprogram the immune microenvironment and significantly improve therapeutic effect. This review presents typical combination therapy strategies, emphasizes the time window of combination therapy and different combinations of therapy that may improve the therapeutic effect, and proposes that radiodiagnostic agents combined with tumor immunotherapy are expected to become a new paradigm and a direction for further research in the future.作者贡献：曾馨莹、文雪君负责文献检索、论文撰写及修订；郭志德、张现忠负责论文选题和审校。利益冲突：所有作者均声明不存在利益冲突 -
图 1 2-[18F]FDG联合PD-L1 ICI治疗可显著延缓肿瘤生长，提高荷瘤小鼠总生存期
A.MC38荷瘤小鼠的治疗程序和时间表示意图；B.不同治疗组MC38荷瘤小鼠的个体肿瘤生长情况以及90 d存活率(αP指PD-L1抗体剂量为10 mg/kg，αP##指PD-L1抗体剂量为20 mg/kg；18F-F指2-[18F]FDG剂量为925 MBq/kg，18F-F##指2-[18F]FDG剂量为1850 MBq/kg；@4 h指PD-L1抗体与2-[18F]FDG的给药时间窗为4 h)；C.2-[18F]FDG诱导MC38荷瘤小鼠免疫治疗的时间依赖性肿瘤生长曲线和生存曲线；D.ELISA法检测血液中细胞因子IFN-γ、TNF-α、IL-6水平的动态变化；E.记忆性T细胞浸润的流式细胞术分析(CD4+CD44highCD62Llow和CD8+CD44highCD62Llow)；F.用FlowJo v10软件定量分析脾脏总细胞中CD4+CD44highCD62Llow细胞和CD8+CD44highCD62Llow细胞比例；G.治愈小鼠的左后侧在第91天再次接种MC38细胞，并监测至第150天；H.2-[18F]FDG联合PD-L1单抗可增强持久免疫记忆
PD-L1:程序性死亡受体配体1；IFN：干扰素；TNF：肿瘤坏死因子；IL：白细胞介素；*P＜0.05；**P＜0.01；***P＜0.001；****P＜0.0001
表 1 近5年发表的放射性药物联合ICI治疗的临床前研究
第一作者 放射性药物 射线类型 ICI 肿瘤类型 给药方案 TIME变化 治疗效果 Wen[56] 2-[18F] β/γ anti-PD-L1 MC38
CT262-[18F]FDG(37 MBq)给药后4 h静脉注射anti-PD-L1 (400 μg)，共2个疗程(d0, d4) PD-L1、CD8+、CD4+ T细胞上调，DCs、M1巨噬细胞上调，促炎细胞因子上调，Tregs、MDSC下调 抑制肿瘤生长，延长生存期，产生免疫记忆 文雪君[57] 99mTc-RGD γ anti-PD-L1 MC38 99mTc-RGD(18.5或37 MBq)给药后4 h静脉注射anti-PD-L1(400 μg)，共2个疗程(d0, d4) PD-L1上调 完全缓解率为75%，90 d内无复发 Wen[32] 64Cu-DOTA-EB-cRGDfK β anti-PD-L1 MC38 TRT(18.5 MBq)后4 h静脉注射anti-PD-L1(200 μg) PD-L1上调，CD8+及CD4+ T细胞上调，Tregs下调，促炎细胞因子上调 完全缓解率为100%, 生存率为100%, 产生免疫记忆 Wen[31] 177Lu-DOTA-EB-cRGDfK β anti-PD-L1 MC38
CT26TRT(9.25 MBq)后4 h静脉注射anti-PD-L1(200 μg) PD-L1上调，CD8+及CD4+T细胞上调，Tregs下调，促炎细胞因子上调 完全缓解率为100%, 生存率为100%, 产生免疫记忆 Wen[58] 131I-αPD-L1 β anti-PD-L1 MC38
CT26TRT(11.1 MBq)与anti-PD-L1(200 μg)同时静脉注射给药 PD-L1上调 延长生存期 Choi[36] 177Lu-LLP2A β anti-CTLA-4+anti-PD-1/PD-L1 B16F10 TRT(30 MBq)在d0给药，ICI(各200 μg)在d1、d4、d7腹腔注射给药 - 显著提高生存率 Guzik[33] 177Lu-DOTA-folate β anti-CTLA-4 NF9006 TRT(5 MBq)在d0给药，anti-CTLA-4(200 μg)在d1、d4、d7腹腔注射给药 - 抑制肿瘤生长，延长中位生存期 Ren[34] 177Lu-DOTA-Y003 β anti-PD-L1 MC38 TRT(3.7 MBq)在d0、d8给药，anti-PD-L1(100 μg)在d2、d4、d6、d10、d12、d14腹腔注射给药 PD-L1上调，CD8+及CD4+ T细胞上调 抑制肿瘤生长，生存率为100% Czernin[39] 225Ac-PSMA-617 α anti-PD-1 RM1-PGLS TRT(30 kBq)在d0给药，anti-PD-1(200 μg)在d1、d4、d8、d11腹腔注射给药 - 抑制肿瘤生长，25%完全缓解 Vito[37] 177Lu-DNP-DOTA-BSA β anti-CTLA-4+anti-PD-L1 E0771 TRT(4.4 MBq)在d0、d4给药，ICI(各200 μg)从d2开始每3天腹腔给药1次，共10次 CD4+T细胞、巨噬细胞及MDSC下调 延长生存期 Brown[22] 90Y-NM600 β anti-CTLA-4 LLC 在d0进行EBRT(12 Gy)以及TRT (1.85 MBq)，anti-CTLA-4(200 μg)在d3、d6、d9腹腔给药 - 减少肿瘤转移，产生免疫记忆 Rouanet[17] 131I-ICF01012 β anti-CTLA-4+anti-PD-1/PD-L1 B16F10 TRT(18.5 MBq)在d0给药，ICI(各200 μg)在d-4、d0、d4、d8腹腔给药 T细胞衰竭相关基因CD274，LAG3和Eomes增加 延长生存期 Potluri[23] 90Y-NM600 β anti-PD-1 TRAMP-C1
Myc-CaPTRT(9.25 MBq)在d0给药，anti-PD-1(200 μg)在d0、d3、d6腹腔给药 CD8+ T细胞、Tregs细胞上调，PD-L1上调 未提高疗效 Chen[30] 177Lu-EB-RGD β anti-PD-L1 MC38 TRT(18.5 MBq)在d0给药，anti-PD-L1(200 μg)在d1、d4、d7腹腔给药 CD8+ T细胞浸润，PD-L1上调 抑制肿瘤生长，生存率为100% Li[47] 212Pb-VMT01 α anti-CTLA-4+anti-PD-1 B16F10 TRT(4.1 MBq)在d0给药，ICI(各200 μg)每周2次腹腔给药 CD3+、CD4+、CD8+淋巴细胞上调 43%完全缓解，延长生存期，产生免疫记忆 Dabagian[41] 211At-MM4 α anti-PD-1 U87MG TRT(0.72 MBq)在d0给药，anti-PD-1(200 μg)在d-3、d0、d3腹腔给药 PD-L1上调，CD8+及CD4+ T细胞上调 完全缓解率为100% Lejeune[51] MSLN-TTC
(227Th)α anti-PD-L1 MC38-hMSLN TRT(5 kBq)在d0给药，anti-PD-L1(30 μg)每周2次腹腔给药 CD8+T细胞上调，IFNγ、CCL3、CCL4、IL-2、IL-5和IL-10上调，TGF-β和FOXP3上调 58.3%完全缓解，延长生存期 Malo[35] 177Lu-h8C3
225Ac-h8C3β
αanti-PD-1 Cloudman S91 177Lu(3.7 MBq)在d0、d7给药，anti-PD-1(250 μg)在d1、d4、d7腹腔给药 未观察到肿瘤T细胞浸润增加 177Lu抑制肿瘤生长，延长生存期，225Ac联合治疗无效 Patel[19] 90Y-NM600 β anti-CTLA-4 + anti-PD-L1 B78
NXS2
4T1TRT(1.85 MBq)在d0给药，anti-CTLA-4(200 μg)在d3、d6、d9腹腔给药；EBRT (12 Gy)及TRT(1.85 MBq)在d0给药，anti-CTLA-4(200 μg)在d3、d6、d9腹腔给药 促炎细胞因子(IFN-γ, IL-10)的产生显著增加，效应T细胞浸润，联合中等剂量EBRT诱导远隔效应 显著抑制肿瘤生长，延长生存期，产生免疫记忆，原发及对侧肿瘤均缓解(46.7%完全缓解) Nosanchuk[48] 213Bi-8C3 α anti-CTLA-4 B16-F10 TRT(5.55 MBq)，anti-CTLA-4(100 μg)在d1、d5、d7腹腔给药 - TRT及联合治疗均减少肺转移，但二者无差异 Zhang[21] 131I- MnO2-BSA β anti-PD-L1 4T1 TRT(18.5 MBq)在d0给药，anti-PD-L1(20 μg)在d1、d3、d5腹腔给药 CTLs浸润增加，Tregs、F4/80+ TAM下调，PD-L1上调，TNF-α、IFN-γ上调 抑制原发性肿瘤和远处肿瘤生长 Zhang[42] 211At-ATE-MnO2-BSA α anti-PD-L1 4T1
CT26TRT(555 kBq)在d0给药，anti-PD-L1(75 μg)在d1、d3、d5腹腔给药 CTLs浸润增加，TNF-α、IFN-γ上调，Tregs无变化，TEM浸润增加，TCM减少 有效抑制原发性肿瘤和远处肿瘤的生长，产生了长期免疫记忆 注：均以第一次TRT治疗为d0，d-3为TRT给药前3 d，d-4为TRT给药前4 d，所有TRT均是静脉注射给药，均估算小鼠体质量为20 g换算剂量；PD-1：程序性死亡[蛋白]-1；CTLA-4：细胞毒性T淋巴细胞抗原4；TRT：靶向放射性核素治疗；ICI：免疫检查点抑制剂；DCs：树突状细胞；Tregs：调节性T细胞；MDSC：髓源性抑制细胞；EBRT：外照射放疗；LAG3：淋巴细胞激活基因-3；CCL：趋化因子C-C-基元配体；TGF-β：转化生长因子-β；TEM：效应记忆T细胞；TCM：中央记忆T细胞；TAM：肿瘤相关巨噬细胞；CTLs：细胞毒性T淋巴细胞；FOXP3：叉头蛋白P3；Emoes：脱中胚蛋白；IFN、TNF、IL、PD-L1：同图 1 
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