USP7 inhibitors suppress tumour neoangiogenesis and promote synergy with immune checkpoint inhibitors by downregulating fibroblast VEGF

Anamarija Jurisic, Pei-Ju Sung, Mark Wappett, Julien Daubriac, Ian T Lobb, Wei-Wei Kung, Nyree Crawford, Natalie Page, Eamon Cassidy, Stephanie Feutren-Burton, J S Shane Rountree, Matthew D Helm, Colin R O'Dowd, Richard D Kennedy, Gerald Gavory, Aaron N Cranston, Daniel B Longley, Xavier Jacq, Timothy Harrison

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Abstract

BACKGROUND: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts.

METHODS: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs).

RESULTS: Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8-positive T-lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival.

CONCLUSIONS: USP7-mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well-characterized VEGF transcription factor, HIF-1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform "immune desert" tumors into "immune responsive" tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs).

Original languageEnglish
Article numbere1648
Number of pages22
JournalClinical and Translational Medicine
Volume14
Issue number4
DOIs
Publication statusPublished - 11 Apr 2024

Keywords

  • Humans
  • Vascular Endothelial Growth Factor A
  • Immune Checkpoint Inhibitors/pharmacology
  • Ubiquitin-Specific Peptidase 7
  • Neoplasms
  • Neovascularization, Pathologic/drug therapy
  • Fibroblasts/metabolism
  • Tumor Microenvironment
  • CCAAT-Enhancer-Binding Proteins/pharmacology
  • Ubiquitin-Protein Ligases/pharmacology

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