Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1 monoclonal antibody for assessing radiation-induced PD-L1 upregulation in head and neck cancer and melanoma

Masahiro Kikuchi, David A. Clump, Raghvendra M. Srivastava, Lingyi Sun, Dexing Zeng, Julio A. Diaz-Perez, Carolyn J. Anderson, W. Barry Edwards, Robert L. Ferris

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma). Tumors were established in two locations per mouse (neck and flank), and fractionated RT (2 Gy × 4 or 2 Gy × 10) was delivered only to the neck tumor, alone or during anti-PD-1 mAb immunotherapy. PD-L1 expression was measured by PET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and results were validated by flow cytometry. PET/CT imaging demonstrated significantly increased tracer uptake in irradiated neck tumors compared with non-irradiated flank tumors. Ex vivo analysis by biodistribution and flow cytometry validated PD-L1 upregulation specifically in irradiated tumors. In the HNSCC model, RT-induced PD-L1 upregulation was only observed after 2 Gy × 10 fractionated RT, while in the B16F10 model upregulation of PD-L1 occurred after 2 Gy × 4 fractionated RT. Fractionated RT, but not anti-PD-1 therapy, upregulated PD-L1 expression on tumor and infiltrating inflammatory cells in murine models, which could be non-invasively monitored by immunoPET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and differentially identified anti-PD-1 responsive as well as selectively irradiated tumors in vivo.

Original languageEnglish (US)
Article numbere1329071
JournalOncoImmunology
Volume6
Issue number7
DOIs
StatePublished - Jul 3 2017
Externally publishedYes

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Head and Neck Neoplasms
Melanoma
Up-Regulation
Monoclonal Antibodies
Radiation
Ligands
Radiotherapy
Neoplasms
Neck
Immunotherapy
Flow Cytometry
Tumor Microenvironment
Myeloid Cells
Therapeutics

Keywords

  • Head and neck cancer
  • melanoma
  • PD-L1
  • PET imaging
  • radiation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1 monoclonal antibody for assessing radiation-induced PD-L1 upregulation in head and neck cancer and melanoma. / Kikuchi, Masahiro; Clump, David A.; Srivastava, Raghvendra M.; Sun, Lingyi; Zeng, Dexing; Diaz-Perez, Julio A.; Anderson, Carolyn J.; Edwards, W. Barry; Ferris, Robert L.

In: OncoImmunology, Vol. 6, No. 7, e1329071, 03.07.2017.

Research output: Contribution to journalArticle

Kikuchi, Masahiro ; Clump, David A. ; Srivastava, Raghvendra M. ; Sun, Lingyi ; Zeng, Dexing ; Diaz-Perez, Julio A. ; Anderson, Carolyn J. ; Edwards, W. Barry ; Ferris, Robert L. / Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1 monoclonal antibody for assessing radiation-induced PD-L1 upregulation in head and neck cancer and melanoma. In: OncoImmunology. 2017 ; Vol. 6, No. 7.
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AU - Sun, Lingyi

AU - Zeng, Dexing

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