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Targeted protein degradation combined with PET imaging reveals the role of host PD-L1 in determining anti-PD-1 therapy efficacy

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Immunohistochemical staining of programmed death-ligand 1 (PD-L1) in tumor biopsies acquired through invasive procedures is routinely employed in clinical practice to identify patients who are most likely to benefit from anti-programmed cell death protein 1 (PD-1) therapy. Nevertheless, PD-L1 expression is observed in various cellular subsets within tumors and their microenvironments, including tumor cells, dendritic cells, and macrophages. The impact of PD-L1 expression across these different cell types on the responsiveness to anti-PD-1 treatment is yet to be fully understood.

Methods

We synthesized polymer-based lysosome-targeting chimeras (LYTACs) that incorporate both PD-L1-targeting motifs and liver cell-specific asialoglycoprotein receptor (ASGPR) recognition elements. Small-animal positron emission tomography (PET) imaging of PD-L1 expression was also conducted using a PD-L1-specific radiotracer 89Zr-αPD-L1/Fab.

Results

The PD-L1 LYTAC platform was capable of specifically degrading PD-L1 expressed on liver cancer cells through the lysosomal degradation pathway via ASGPR without impacting the PD-L1 expression on host cells. When coupled with whole-body PD-L1 PET imaging, our studies revealed that host cell PD-L1, rather than tumor cell PD-L1, is pivotal in the antitumor response to anti-PD-1 therapy in a mouse model of liver cancer.

Conclusion

The LYTAC strategy, enhanced by PET imaging, has the potential to surmount the limitations of knockout mouse models and to provide a versatile approach for the selective degradation of target proteins in vivo. This could significantly aid in the investigation of the roles and mechanisms of protein functions associated with specific cell subsets in living subjects.

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Data availability

Data generated in the present study are available from the corresponding author (Z.L.) upon reasonable request.

References

  1. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345–62.

    Article  CAS  PubMed  Google Scholar 

  2. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.

    Article  PubMed  Google Scholar 

  3. Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2021;7:113–23.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Greten TF, Abou-Alfa GK, Cheng AL, Duffy AG, El-Khoueiry AB, Finn RS, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma. J Immunother Cancer. 2021;9:e002794.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zhou M, Liu B, Shen J. Immunotherapy for hepatocellular carcinoma. Clin Exp Med. 2023;23:569–77.

    Article  CAS  PubMed  Google Scholar 

  7. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18:525–43.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184:5309–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18:345–62.

    Article  CAS  PubMed  Google Scholar 

  10. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56.

    Article  CAS  PubMed  Google Scholar 

  11. Wei W, Rosenkrans ZT, Liu J, Huang G, Luo QY, Cai W. ImmunoPET: concept, design, and applications. Chem Rev. 2020;120:3787–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok IC, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24:1852–8.

    Article  CAS  PubMed  Google Scholar 

  13. Kumar D, Lisok A, Dahmane E, McCoy M, Shelake S, Chatterjee S, et al. Peptide-based PET quantifies target engagement of PD-L1 therapeutics. J Clin Invest. 2019;129:616–30.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019;19:133–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–52.

    Article  PubMed  Google Scholar 

  17. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10:727–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Tang H, Liang Y, Anders RA, Taube JM, Qiu X, Mulgaonkar A, et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest. 2018;128:580–8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L, et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest. 2018;128:805–15.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Oh SA, Wu DC, Cheung J, Navarro A, **ong H, Cubas R, et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat Cancer. 2020;1:681–91.

    Article  CAS  PubMed  Google Scholar 

  21. Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020;11:4835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dale B, Cheng M, Park KS, Kaniskan H, **ong Y, ** J. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 2021;21:638–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020;584:291–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano JC, Cotton AD, et al. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat Biotechnol. 2023;41:273–81.

    Article  CAS  PubMed  Google Scholar 

  25. Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, Bertozzi CR. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol. 2021;17:937–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wilkinson KD. The discovery of ubiquitin-dependent proteolysis. Proc Natl Acad Sci U S A. 2005;102:15280–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Caianiello DF, Zhang M, Ray JD, Howell RA, Swartzel JC, Branham EMJ, et al. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat Chem Biol. 2021;17:947–53.

    Article  CAS  PubMed  Google Scholar 

  28. Du J, Choi B, Liu Y, Feng A, Thang SH. Degradable pH and redox dual responsive nanoparticles for efficient covalent drug delivery. Polym Chem. 2019;10:1291–8.

    Article  CAS  Google Scholar 

  29. Chen C, Kong F, Wei X, Thang SH. Syntheses and effectiveness of functional peptide-based RAFT agents. Chem Commun (Camb). 2017;53:10776–9.

    Article  CAS  PubMed  Google Scholar 

  30. Zhao Y, Zhang T, Wang Y, Lu D, Du J, Feng X, et al. ICAM-1 orchestrates the abscopal effect of tumor radiotherapy. Proc Natl Acad Sci U S A. 2021;118:e2010333118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bao R, Wang Y, Lai J, Zhu H, Zhao Y, Li S, et al. Enhancing anti-PD-1/PD-L1 immune checkpoint inhibitory cancer therapy by CD276-targeted photodynamic ablation of tumor cells and tumor vasculature. Mol Pharm. 2019;16:339–48.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou H, Wang Y, Xu H, Shen X, Zhang T, Zhou X, et al. Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy. J Clin Invest. 2022;132:e161065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Feng X, Wang Y, Lu D, Xu X, Zhou X, Zhang H, et al. Clinical translation of a 68Ga-labeled integrin alphavbeta6-targeting cyclic radiotracer for PET imaging of pancreatic cancer. J Nucl Med. 2020;61:1461–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gao H, Wu Y, Shi J, Zhang X, Liu T, Hu B, et al. Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy. J Immunother Cancer. 2020;8:e001156.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhang P, Rashidi A, Zhao J, Silvers C, Wang H, Castro B, et al. STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma. Nat Commun. 2023;14:1610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kordbacheh T, Honeychurch J, Blackhall F, Faivre-Finn C, Illidge T. Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol. 2018;29:301–10.

    Article  CAS  PubMed  Google Scholar 

  37. Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shen X, Zhang L, Li J, Li Y, Wang Y, Xu ZX. Recent findings in the regulation of programmed death ligand 1 expression. Front Immunol. 2019;10:1337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Guo J, Luo L, Wang Z, Hu N, Wang W, **e F, et al. Design, synthesis, and biological evaluation of linear aliphatic amine-linked triaryl derivatives as potent small-molecule inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction with promising antitumor effects in vivo. J Med Chem. 2020;63:13825–50.

    Article  CAS  PubMed  Google Scholar 

  41. Chen Y, Liu Y, Wang Y, Chen X, Wang C, Chen X, et al. Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages. J Exp Clin Cancer Res. 2022;41:1.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Qin M, Cao Q, Wu X, Liu C, Zheng S, **e H, et al. Discovery of the programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing an indoline scaffold. Eur J Med Chem. 2020;186:111856.

    Article  CAS  PubMed  Google Scholar 

  43. Lin W, Chen L, Zhang H, Qiu X, Huang Q, Wan F, et al. Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation. Nat Commun. 2023;14:265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen M, Mao A, Xu M, Weng Q, Mao J, Ji J. CRISPR-Cas9 for cancer therapy: opportunities and challenges. Cancer Lett. 2019;447:48–55.

    Article  CAS  PubMed  Google Scholar 

  45. Wu T, Yoon H, **ong Y, Dixon-Clarke SE, Nowak RP, Fischer ES. Targeted protein degradation as a powerful research tool in basic biology and drug target discovery. Nat Struct Mol Biol. 2020;27:605–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lin J, ** J, Shen Y, Zhang L, Gong G, Bian H, et al. Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics. 2021;11:8337–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003;2:214–21.

    Article  CAS  PubMed  Google Scholar 

  48. Dilliard SA, Siegwart DJ. Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs. Nat Rev Mater. 2023;8:282–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Key R&D Program of China (2023YFC3404600 to Z.L.), National Natural Science Foundation of China (81920108020 and 82325028 to Z.L.), Bei**g Natural Science Foundation (Z220011 and Z220014 to Z.L.), the Capital’s Funds for Health Improvement and Research (2022-2Z-2154 and 2022-2Z-2155 to Z.Y.) and Bei**g Nova Program Interdisciplinary Cooperation Project (20220484182 to H.Z. and Z.L.).

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Author notes

  1. **hong Du and Shu Han contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Bei**g, 100191, China

    **hong Du, Shu Han, Haoyi Zhou, Jianze Wang, Rui Song, Kui Li & Zhaofei Liu

  2. Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Bei**g), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Peking University Cancer Hospital and Institute, Bei**g, 100142, China

    Feng Wang, Hua Zhu, Zhi Yang & Zhaofei Liu

  3. Department of Nuclear Medicine, Peking University Third Hospital, Bei**g, 100191, China

    Meixin Zhao, Weifang Zhang & Zhaofei Liu

  4. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Bei**g, 100191, China

    Zhaofei Liu

  5. Peking University-Yunnan Baiyao International Medical Research Center, Bei**g, 100191, China

    Zhaofei Liu

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  1. **hong Du
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Correspondence to Weifang Zhang, Zhi Yang or Zhaofei Liu.

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All animal studies were performed in accordance with the Guidelines of Peking University Health Science Center Animal Care and Use Committee (No. LA2021198).

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Du, J., Han, S., Zhou, H. et al. Targeted protein degradation combined with PET imaging reveals the role of host PD-L1 in determining anti-PD-1 therapy efficacy. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06804-9

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