Journal Article

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

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

2024

Overview

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). The oral USP7 inhibitor, ADC‐159, reduces sVEGF from CAFs and impacts tumor vasculature. USP7 inhibition affects HIF‐1α transcriptional modulation, tumor hypoxia and remodeling of the tumor microenvironment creating a permissive immune micro‐climate for infiltrating lymphocytes turning immunologically ‘cold’ tumors, ‘hot’. In preclinical models, combination treatment of ADC‐159 with immunotherapy agents delivers improved anti‐tumor efficacy and survival.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: ADC‐159 / CAFs / Cancer / CCAAT-Enhancer-Binding Proteins - pharmacology / Cell adhesion & migration / CRISPR / deubiquitylating enzymes / DUBs / Fibroblasts / Fibroblasts - metabolism / Gene expression / HAUSP / HIF‐1α / Humans / Hypoxia / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / immune therapy / Immunotherapy / neoangiogenesis / Neoplasms / Neovascularization, Pathologic - drug therapy / Proteins / TME / Tumor Microenvironment / Tumors / tumour microenvironment / Ubiquitin-Protein Ligases - pharmacology / Ubiquitin-Specific Peptidase 7 / USP7 / Vascular Endothelial Growth Factor A / VEGF