Dataset Information

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

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).

SUBMITTER: Jurisic A

PROVIDER: S-EPMC11007818 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Jurisic Anamarija A Sung Pei-Ju PJ Wappett Mark M Daubriac Julien J Lobb Ian T IT Kung Wei-Wei WW Crawford Nyree N Page Natalie N Cassidy Eamon E Feutren-Burton Stephanie S Rountree J S Shane JSS Helm Matthew D MD O'Dowd Colin R CR Kennedy Richard D RD Gavory Gerald G Cranston Aaron N AN Longley Daniel B DB Jacq Xavier X Harrison Timothy T

Clinical and translational medicine 20240401 4

<h4>Background</h4>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.<h4>Methods</h4>To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on ...[more]

PMID: 38602256

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Project description:Purpose:Renal injury with the loss of podocyte was characteristic pathology of diabetic nephropathy (DN) and correlated with increased albuminuria. Many studies have found the nephroprotective effect of the novel inhibitors of sodium-glucose cotransporter 2 (SGLT2-is), like Dapagliflozin, delaying the progression of DN. However, the underlying mechanisms of SGLT2 associated with podocyte injury are still not fully elucidated. Methods: Through mRNA sequencing, streptozotocin-induced and Dapagliflozin-intraperitoneal injection mice models were established to explore potential mechanism between Dapagliflozin and renal phenotype. And all changes referring this observed pathway were proven repeatedly in podocyte. Results: Here, we generated the streptozotocin-induced DN models and found the accumulation of nephrotoxin and pathological lesions of the kidney, including interstitial inflammatory infiltration, mesangial expansion and glomerular sclerosis, while low expression of SGLT2 mitigated these injuries in Dapagliflozin-treated mice. Moreover, mRNA expression profile in these treated models determined the significance of insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. Particularly, SGLT2-is inhibited the increase of mesenchymal marker, α-SMA and the decrease of podocyte marker, nephrin at the gene or protein level. KEGG analysis also showed the enrichment of phosphatidylinositol signaling system and TGF-β/smad pathway. In parallel, the protein level of IGF1R, phosphorylated PI3K, and α-SMA were increased in high-glucose stimulated human podocyte, and reduced in Dapagliflozin (50nM and 100nM) or OSI-906 (inhibitor of IGF1R, 60nM) used groups. Notably, combination of the two inhibitors produced an accumulative effect in the protection of podocyte integrity. Mechanistically, IGF1 or IGF2 could bind to IGF1 receptors to mediate the epithelial-mesenchymal transition (EMT) of diabetic podocyte in response to the upregulation of SGLT2. Indeed, we enrolled the urine and plasma samples from a cohort consisting of 13 healthy people, and a cohort of 19 patients with DN using SGLT2-inhibitors (n=9) or not (n=10). Compared with pure DN patients, Elisa results suggested an increased circulation and excretion level of IGF1/2 in SGLT2-is used DN cohort. Conclusions: Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte EMT. Modulating the IGF1R expression may provide a novel idea for DN therapy.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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