Research Paper Volume 13, Issue 9 pp 13006—13022
A preclinical study: correlation between PD-L1 PET imaging and the prediction of therapy efficacy of MC38 tumor with 68Ga-labeled PD-L1 targeted nanobody
- 1 Tianjin Medical University, Tianjin 300070, P.R. China
- 2 Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China
- 3 School of Graduate Studies, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 271099, P.R. China
- 4 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250017, P.R. China
- 5 Department of Radiation Oncology, The Fourth People’s Hospital of Jinan, Jinan 250031, P.R. China
- 6 School of Pharmacy, Yantai University, Yantai 264003, P.R. China
- 7 Smart Nuclide Biotech, Suzhou 215123, P.R. China
- 8 School of Clinical Medicine, Weifang Medical University, Weifang 261053, P.R. China
- 9 Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250017, P.R. China
Received: May 28, 2020 Accepted: February 16, 2021 Published: April 27, 2021
https://doi.org/10.18632/aging.202981How to Cite
Abstract
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.
Abbreviations
PD-1: programmed cell death protein-1; PD-L1: programmed death protein ligand 1; TILs: tumor infiltrating immune cells; PET: positron emission tomography; IHC: immune- histochemistry; HuMAb: human immunoglobulin monoclonal antibody; IF: immunofluorescence; HPLC: High-Performance Liquid Chromatography; SEC: size-exclusion chromatogram; RTV: relative tumor volume; hPD-L1: human PD-L1; KO: knock out.