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Recently, the team of Professor Shi Benkang from Qilu Hospital of Shandong University published the latest research results "FGFR3 Destabilizes PD-L1 Via NEDD4 to Control T Cell-Mediated Bladder Cancer Immune Surveillance" online in the international authoritative oncology journal Cancer Research (IF: 12.
843), revealing the bladder The effect of cancer FGFR targeted therapy on tumor immune microenvironment
.
In recent years, with the development of molecular classification and precise treatment of bladder urothelial cancer, in addition to traditional chemotherapy, immunotherapy and targeted therapy have also played an increasingly important role in the treatment of urothelial cancer
.
FGFR inhibitor (which can target fibroblast growth factor 3 [FGFR3] activating mutations) Erdatinib is the only FGFR TKI drug approved for use in the treatment of bladder cancer
.
Studies have shown that about 40% of patients with FGFR3 mutant bladder cancer can get remission from the treatment of erdatinib, but more than half of the patients still cannot benefit from the targeted therapy
.
Based on the needs faced by bladder cancer treatment, Professor Shi Benkang’s team revealed for the first time that FGFR3 targeted therapy combined with immune checkpoint inhibitors can significantly enhance the anti-tumor effect in the treatment of bladder cancer.
At the same time, further mechanism analysis clarified the possibility of this combination scheme.
Internal mechanism
.
Previous studies have shown that patients with FGFR3 mutation or high expression of urothelial carcinoma have weaker immunophenotypes, but the specific mechanism is not clear
.
FGFR3 is usually mutated or overexpressed in urothelial cancer, and it is an established target for urothelial cancer
.
The study found that FGFR3 pathway activation can lead to down-regulation of PD-L1 expression.
Correspondingly, histological analysis of bladder cancer patients also showed that FGFR3 expression is negatively correlated with PD-L1 expression
.
When FGFR3 inhibitors are used in FGFR3 activated mutant bladder cancer, they can increase the expression of PD-L1 by affecting its ubiquitination, thereby reducing the anti-tumor activity of CD8+ T cells
.
More importantly, the study found that NEDD4, a key molecule that can be combined with targeted therapy and immunotherapy to fight tumors, is a key E3 ubiquitin ligase that can target FGFR3 to activate PD-L1 in mutant bladder cancer
.
NEDD4 is a member of the NEDD4 E3 ubiquitin ligase family.
It can be activated by FGFR3 to be phosphorylated and act as a regulator of PD-L1 ubiquitination
.
Specifically, NEDD4 interacts with PD-L1 and catalyzes Lys48 of PD-L1 to make it polyubiquitinated, thereby causing ubiquitination degradation
.
The expression of PD-L1 in NEDD4 knockout mice with bladder cancer was up-regulated, and CD8+ T cell infiltration and anti-tumor activity were also significantly inhibited
.
It can be seen that FGFR3 regulates the ubiquitination of PD-L1 through NEDD and affects the expression of PD-L1 and thus affects anti-tumor activity
.
Many preclinical studies have shown that FGFR3 targeted therapy can be combined with PD-1 immunotherapy to enhance the anti-tumor activity of CD8+ T, thereby effectively inhibiting tumor growth
.
The researchers further pointed out that more than half of FGFR3 mutant urothelial cancer patients cannot benefit from FGFR inhibitors, and the anti-tumor effect of FGFR inhibitors can be improved through combined immunotherapy
.
Summary This study found for the first time that the activated FGFR3 in bladder cancer can recruit and activate NEDD4 to play a ubiquitination effect on PD-L1 and achieve the degradation of PD-L1
.
When targeted drugs such as erdatinib are used, they can inhibit the phosphorylation of NEDD4 while inhibiting the FGFR3 signaling pathway, and up-regulate the expression of PD-L1 on the surface of tumor cells
.
The researchers further confirmed through a variety of animal experiments that targeted combined immunotherapy has good anti-tumor effects in mouse models of bladder cancer, providing a solid theoretical basis for the next step of clinical combination drugs
.
Reference: FGFR3 Destabilizes PD-L1 Via NEDD4 to Control T Cell-Mediated Bladder Cancer Immune Surveillance.
DOI: 10.
1158/0008-5472.
CAN-21-2362
843), revealing the bladder The effect of cancer FGFR targeted therapy on tumor immune microenvironment
.
In recent years, with the development of molecular classification and precise treatment of bladder urothelial cancer, in addition to traditional chemotherapy, immunotherapy and targeted therapy have also played an increasingly important role in the treatment of urothelial cancer
.
FGFR inhibitor (which can target fibroblast growth factor 3 [FGFR3] activating mutations) Erdatinib is the only FGFR TKI drug approved for use in the treatment of bladder cancer
.
Studies have shown that about 40% of patients with FGFR3 mutant bladder cancer can get remission from the treatment of erdatinib, but more than half of the patients still cannot benefit from the targeted therapy
.
Based on the needs faced by bladder cancer treatment, Professor Shi Benkang’s team revealed for the first time that FGFR3 targeted therapy combined with immune checkpoint inhibitors can significantly enhance the anti-tumor effect in the treatment of bladder cancer.
At the same time, further mechanism analysis clarified the possibility of this combination scheme.
Internal mechanism
.
Previous studies have shown that patients with FGFR3 mutation or high expression of urothelial carcinoma have weaker immunophenotypes, but the specific mechanism is not clear
.
FGFR3 is usually mutated or overexpressed in urothelial cancer, and it is an established target for urothelial cancer
.
The study found that FGFR3 pathway activation can lead to down-regulation of PD-L1 expression.
Correspondingly, histological analysis of bladder cancer patients also showed that FGFR3 expression is negatively correlated with PD-L1 expression
.
When FGFR3 inhibitors are used in FGFR3 activated mutant bladder cancer, they can increase the expression of PD-L1 by affecting its ubiquitination, thereby reducing the anti-tumor activity of CD8+ T cells
.
More importantly, the study found that NEDD4, a key molecule that can be combined with targeted therapy and immunotherapy to fight tumors, is a key E3 ubiquitin ligase that can target FGFR3 to activate PD-L1 in mutant bladder cancer
.
NEDD4 is a member of the NEDD4 E3 ubiquitin ligase family.
It can be activated by FGFR3 to be phosphorylated and act as a regulator of PD-L1 ubiquitination
.
Specifically, NEDD4 interacts with PD-L1 and catalyzes Lys48 of PD-L1 to make it polyubiquitinated, thereby causing ubiquitination degradation
.
The expression of PD-L1 in NEDD4 knockout mice with bladder cancer was up-regulated, and CD8+ T cell infiltration and anti-tumor activity were also significantly inhibited
.
It can be seen that FGFR3 regulates the ubiquitination of PD-L1 through NEDD and affects the expression of PD-L1 and thus affects anti-tumor activity
.
Many preclinical studies have shown that FGFR3 targeted therapy can be combined with PD-1 immunotherapy to enhance the anti-tumor activity of CD8+ T, thereby effectively inhibiting tumor growth
.
The researchers further pointed out that more than half of FGFR3 mutant urothelial cancer patients cannot benefit from FGFR inhibitors, and the anti-tumor effect of FGFR inhibitors can be improved through combined immunotherapy
.
Summary This study found for the first time that the activated FGFR3 in bladder cancer can recruit and activate NEDD4 to play a ubiquitination effect on PD-L1 and achieve the degradation of PD-L1
.
When targeted drugs such as erdatinib are used, they can inhibit the phosphorylation of NEDD4 while inhibiting the FGFR3 signaling pathway, and up-regulate the expression of PD-L1 on the surface of tumor cells
.
The researchers further confirmed through a variety of animal experiments that targeted combined immunotherapy has good anti-tumor effects in mouse models of bladder cancer, providing a solid theoretical basis for the next step of clinical combination drugs
.
Reference: FGFR3 Destabilizes PD-L1 Via NEDD4 to Control T Cell-Mediated Bladder Cancer Immune Surveillance.
DOI: 10.
1158/0008-5472.
CAN-21-2362
