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iNature anti-PD-1/PD-L1 immunotherapy has achieved impressive results in patients with multiple cancer types
.
However, the molecular mechanisms underlying moderate response rates (15-25%) or resistance to PD-1/PD-L1 blockade are not fully understood
.
On March 31, 2022, teams from Wuhan University Zhang Jinfang, Shu Hongbing and Wang Haizhen from the Medical University of South Carolina jointly published a research paper titled "USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy" in Nature Communications.
The deubiquitinase USP8 significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy by remodeling the inflammatory tumor microenvironment (TME)
.
Mechanistically, USP8 inhibition increases PD-L1 protein abundance by enhancing TRAF6-mediated K63-linked PD-L1 ubiquitination to antagonize K48-linked ubiquitination and PD-L1 degradation
.
In addition, USP8 inhibition also triggers innate immune responses and MHC-I expression primarily by activating NF-κB signaling
.
Based on these mechanisms, USP8 inhibitor combined with PD-1/PD-L1 blockade can significantly activate infiltrating CD8+ T cells to inhibit tumor growth and improve survival benefit in several mouse tumor models
.
Therefore, this study revealed a potential combination therapy strategy utilizing USP8 inhibitors and PD-1/PD-L1 blockers to enhance antitumor efficacy
.
Cancer immunotherapies, especially those targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway, have achieved impressive results in patients with multiple cancer types
.
However, the molecular mechanisms underlying moderate response rates (15-25%) or resistance to PD-1/PD-L1 blockade are not fully understood
.
Growing evidence suggests that PD-L1 expression levels, intact antigen presentation, highly cytotoxic T lymphocyte (CTL) infiltration, or interferon (IFN) signaling activation in tumor cells or the tumor microenvironment (TME) may be responsible for Better response to PD-1/PD-L1 therapy
.
Therefore, a thorough understanding of the regulatory mechanisms of PD-L1 and other markers may help to overcome the bottleneck of anti-PD-1/PD-L1 immunotherapy by designing combination therapeutic strategies
.
Ubiquitination is an important type of post-translational modification (PTM) that plays a key role in regulating various cellular processes by controlling protein stability, trafficking, localization, and interactions
.
One ubiquitin molecule has seven lysine (K) residues (K6, K11, K27, K29, K33, K48, and K63) by combining the C-terminal glycine of the second ubiquitin molecule with the first ubiquitin moiety Covalently bound to one of the seven lysine residues on the amino-terminal methionine (Met1), it can assemble into eight distinct ubiquitin chains
.
Different ubiquitin chain linkages perform different cellular functions
.
It is well known that K48- or K11-linked ubiquitin chains act as destruction signals to trigger 26S proteasome-mediated proteolysis, while K63-linked ubiquitination acts as a non-degradative signal in NF-κB activation and immune responses
.
Recent studies have shown that several E3 ligases destabilize PD-L1 primarily through 26S proteasome- or lysosome-mediated degradation
.
However, whether PD-L1 can be modified by other non-degradable ubiquitin chains to control its physiological functions remains incompletely understood
.
Schematic diagram of the article (image from Nature Communications) Compared to ubiquitin E3 ligases that conjugate ubiquitin chains to their target proteins, deubiquitinating proteases (DUBs) can cleave and remove ubiquitin from their substrate proteins prime chain
.
In mammals, more than 100 DUBs have been discovered, and ubiquitin-specific proteases (USPs) are the largest DUB subfamily with about 54 members
.
USP8 (also known as UBPY), a member of the USP subfamily, plays a key role in controlling endocytosis and protein trafficking, primarily through its deubiquitination activity in the endosomal sorting complex required for regulatory transport (ESCRT).
play an important role
.
Previous studies have also shown that USP8 is frequently overexpressed in human cancers, and that cancer patients with high USP8 expression have lower overall survival
.
However, whether USP8 is involved in the regulation of cancer immunotherapy has not been reported
.
This study reports that inhibition of the deubiquitinase USP8 significantly improves the efficacy of anti-PD-1/PD-L1 immunotherapy by remodeling the inflammatory tumor microenvironment (TME)
.
Mechanistically, USP8 inhibition increases PD-L1 protein abundance by enhancing TRAF6-mediated K63-linked PD-L1 ubiquitination to antagonize K48-linked ubiquitination and PD-L1 degradation
.
In addition, USP8 inhibition also triggers innate immune responses and MHC-I expression primarily by activating NF-κB signaling
.
Based on these mechanisms, USP8 inhibitor combined with PD-1/PD-L1 blockade can significantly activate infiltrating CD8+ T cells to inhibit tumor growth and improve survival benefit in several mouse tumor models
.
Therefore, this study revealed a potential combination therapy strategy utilizing USP8 inhibitors and PD-1/PD-L1 blockers to enhance antitumor efficacy
.
Reference message: https://
.
However, the molecular mechanisms underlying moderate response rates (15-25%) or resistance to PD-1/PD-L1 blockade are not fully understood
.
On March 31, 2022, teams from Wuhan University Zhang Jinfang, Shu Hongbing and Wang Haizhen from the Medical University of South Carolina jointly published a research paper titled "USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy" in Nature Communications.
The deubiquitinase USP8 significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy by remodeling the inflammatory tumor microenvironment (TME)
.
Mechanistically, USP8 inhibition increases PD-L1 protein abundance by enhancing TRAF6-mediated K63-linked PD-L1 ubiquitination to antagonize K48-linked ubiquitination and PD-L1 degradation
.
In addition, USP8 inhibition also triggers innate immune responses and MHC-I expression primarily by activating NF-κB signaling
.
Based on these mechanisms, USP8 inhibitor combined with PD-1/PD-L1 blockade can significantly activate infiltrating CD8+ T cells to inhibit tumor growth and improve survival benefit in several mouse tumor models
.
Therefore, this study revealed a potential combination therapy strategy utilizing USP8 inhibitors and PD-1/PD-L1 blockers to enhance antitumor efficacy
.
Cancer immunotherapies, especially those targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway, have achieved impressive results in patients with multiple cancer types
.
However, the molecular mechanisms underlying moderate response rates (15-25%) or resistance to PD-1/PD-L1 blockade are not fully understood
.
Growing evidence suggests that PD-L1 expression levels, intact antigen presentation, highly cytotoxic T lymphocyte (CTL) infiltration, or interferon (IFN) signaling activation in tumor cells or the tumor microenvironment (TME) may be responsible for Better response to PD-1/PD-L1 therapy
.
Therefore, a thorough understanding of the regulatory mechanisms of PD-L1 and other markers may help to overcome the bottleneck of anti-PD-1/PD-L1 immunotherapy by designing combination therapeutic strategies
.
Ubiquitination is an important type of post-translational modification (PTM) that plays a key role in regulating various cellular processes by controlling protein stability, trafficking, localization, and interactions
.
One ubiquitin molecule has seven lysine (K) residues (K6, K11, K27, K29, K33, K48, and K63) by combining the C-terminal glycine of the second ubiquitin molecule with the first ubiquitin moiety Covalently bound to one of the seven lysine residues on the amino-terminal methionine (Met1), it can assemble into eight distinct ubiquitin chains
.
Different ubiquitin chain linkages perform different cellular functions
.
It is well known that K48- or K11-linked ubiquitin chains act as destruction signals to trigger 26S proteasome-mediated proteolysis, while K63-linked ubiquitination acts as a non-degradative signal in NF-κB activation and immune responses
.
Recent studies have shown that several E3 ligases destabilize PD-L1 primarily through 26S proteasome- or lysosome-mediated degradation
.
However, whether PD-L1 can be modified by other non-degradable ubiquitin chains to control its physiological functions remains incompletely understood
.
Schematic diagram of the article (image from Nature Communications) Compared to ubiquitin E3 ligases that conjugate ubiquitin chains to their target proteins, deubiquitinating proteases (DUBs) can cleave and remove ubiquitin from their substrate proteins prime chain
.
In mammals, more than 100 DUBs have been discovered, and ubiquitin-specific proteases (USPs) are the largest DUB subfamily with about 54 members
.
USP8 (also known as UBPY), a member of the USP subfamily, plays a key role in controlling endocytosis and protein trafficking, primarily through its deubiquitination activity in the endosomal sorting complex required for regulatory transport (ESCRT).
play an important role
.
Previous studies have also shown that USP8 is frequently overexpressed in human cancers, and that cancer patients with high USP8 expression have lower overall survival
.
However, whether USP8 is involved in the regulation of cancer immunotherapy has not been reported
.
This study reports that inhibition of the deubiquitinase USP8 significantly improves the efficacy of anti-PD-1/PD-L1 immunotherapy by remodeling the inflammatory tumor microenvironment (TME)
.
Mechanistically, USP8 inhibition increases PD-L1 protein abundance by enhancing TRAF6-mediated K63-linked PD-L1 ubiquitination to antagonize K48-linked ubiquitination and PD-L1 degradation
.
In addition, USP8 inhibition also triggers innate immune responses and MHC-I expression primarily by activating NF-κB signaling
.
Based on these mechanisms, USP8 inhibitor combined with PD-1/PD-L1 blockade can significantly activate infiltrating CD8+ T cells to inhibit tumor growth and improve survival benefit in several mouse tumor models
.
Therefore, this study revealed a potential combination therapy strategy utilizing USP8 inhibitors and PD-1/PD-L1 blockers to enhance antitumor efficacy
.
Reference message: https://
