A preclinical study: correlation between PD-L1 PET imaging and the prediction of therapy efficacy of MC38 tumor with (68)Ga-labeled PD-L1 targeted nanobody.
A preclinical study: correlation between PD-L1 PET imaging and the prediction of therapy efficacy of MC38 tumor with (68)Ga-labeled PD-L1 targeted nanobody.
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临床前研究：PD-L1 PET成像与（68）ga标记PD-L1靶向纳米体预测MC38肿瘤治疗效果的相关性
DOI：
10.18632/aging.202981
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发表时间：
2021-04-27
期刊：
影响因子：
--
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Qin S;Yu Y;Guan H;Yang Y;Sun F;Sun Y;Zhu J;Xing L;Yu J;Sun X
尽管免疫疗法在临床结局方面取得了巨大的临床成功，特别是抗PD-1或抗PD-L1抗体，但并非所有患者都对抗PD-1免疫疗法有反应。临床诊断迫切需要开发无创成像介导的评估肿瘤中PD-L1表达水平的策略。在这项工作中，设计了一种68 Ga标记的单域抗体示踪剂68 Ga-NOTA-Nb 109，用于在MC 38荷瘤小鼠模型中对PD-L1表达进行特异性和非侵入性成像。在不同PD-L1表达荷瘤模型中进行了包括正电子发射断层扫描（PET）、生物分布、阻断研究、免疫组织化学和免疫治疗在内的综合研究。这些结果表明，68 Ga-NOTA-Nb 109特异性地积累在MC 38-hPD-L1肿瘤中。在注射后0.5、1、1.5、2小时，该纳米抗体在MC 38 hPD-L1肿瘤和MC 38混合肿瘤中的含量分别为8.2 ± 1.3、7.3 ± 1.2、3.7 ± 1.5、2.3 ± 1.2%ID/g和7.5 ± 1.4、3.6 ± 1.7、1.7 ± 0.6、1.2 ± 0.5%ID/g。68 Ga-NOTA-Nb 109有可能进一步基于肿瘤中的PD-L1状态进行无创PET成像和治疗有效性评估。为了探索免疫疗法与化学疗法组合的可能的协同效应，建立了对PD-L1阻断具有不同敏感性的MC 38异种移植物。此外，我们发现PD-1阻断对PD-L1敲除肿瘤也有效。采用RT-PCR和免疫荧光法检测PD-L1的表达。观察到小鼠和人PD-L1在三种类型的MC 38肿瘤中均表达。这些结果表明，肿瘤细胞上的PD-L1影响疗效，但它对宿主骨髓细胞可能是检查点阻断所必需的。此外，抗PD-1治疗激活肿瘤微环境中的肿瘤反应性CD 103 + CD 39 + CD 8 +T细胞（TIL）。
Although immunotherapy has achieved great clinical success in clinical outcomes, especially the anti-PD-1 or anti-PD-L1 antibodies, not all patients respond to anti-PD-1 immunotherapy. It is urgently required for a clinical diagnosis to develop non-invasive imaging meditated strategy for assessing the expression level of PD-L1 in tumors. In this work, a 68Ga-labeled single-domain antibody tracer, 68Ga-NOTA-Nb109, was designed for specific and noninvasive imaging of PD-L1 expression in an MC38 tumor-bearing mouse model. Comprehensive studies including Positron Emission Tomography (PET), biodistribution, blocking studies, immunohistochemistry, and immunotherapy, have been performed in differences PD-L1 expression tumor-bearing models. These results revealed that 68Ga-NOTA-Nb109 specifically accumulated in the MC38-hPD-L1 tumor. The content of this nanobody in MC38 hPD-L1 tumor and MC38 Mixed tumor was 8.2 ± 1.3, 7.3 ± 1.2, 3.7 ± 1.5, 2.3 ± 1.2%ID/g and 7.5 ± 1.4, 3.6 ± 1.7, 1.7 ± 0.6, 1.2 ± 0.5%ID/g at 0.5, 1, 1.5, 2 hours post-injection, respectively. 68Ga-NOTA-Nb109 has the potential to further noninvasive PET imaging and therapy effectiveness assessments based on the PD-L1 status in tumors. To explore the possible synergistic effects of immunotherapy combined with chemotherapy, MC38 xenografts with different sensitivity to PD-L1 blockade were established. In addition, we found that PD-1 blockade also had efficacy on the PD-L1 knockout tumors. RT-PCR and immunofluorescence analysis were used to detect the expression of PD-L1. It was observed that both mouse and human PD-L1 expressed among three types of MC38 tumors. These results suggest that PD-L1 on tumor cells affect the efficacy, but it on host myeloid cells might be essential for checkpoint blockade. Moreover, anti–PD-1 treatment activates tumor-reactive CD103+ CD39+ CD8+T cells (TILs) in tumor microenvironment.