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Updated: Nov 26, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma
Weinan Guo1, Jinyuan Ma2, Sen Guo2
1Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China lichying@fmmu.edu.cn guown@fmmu.edu.cn.
Background:
The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.
Methods:
The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.
Results:
We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden.
Conclusions:
Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.
Insights
Targeting A20, an inflammation-related molecule, can enhance anti-programmed cell death (PD-1) immunotherapy in melanoma. This approach invigorates CD8+ T cells and improves responses in patients resistant to current treatments.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint blockers like anti-PD-1/PD-L1 antibodies show therapeutic effects in melanoma.
- However, limited response rates and acquired resistance impede their clinical efficacy.
- The role of inflammation-related molecule A20 in antitumor immunity and immunotherapy response remains unclear.
Purpose of the Study:
- To investigate the association between tumorous A20 expression and anti-PD-1 immunotherapy outcomes in melanoma.
- To elucidate the mechanism by which A20 influences antitumor immunity and immunotherapy efficacy.
- To explore A20 as a potential therapeutic target for improving anti-PD-1 treatment in melanoma.
Main Methods:
- Analysis of melanoma patient tumor specimens using immunoblotting, immunofluorescence, and flow cytometry.
- Preclinical mouse models and in vitro coculture systems to study A20's role in anti-PD-1 immunotherapy.
- Bioinformatics, mass spectrometry, and biochemical analyses to determine the underlying molecular mechanisms.
Main Results:
- Upregulated A20 correlated with reduced CD8+ T cell antitumor activity and poor response to anti-PD-1 therapy.
- Targeting tumorous A20 enhanced immunotherapy by invigorating CD8+ T cells through PD-L1 regulation.
- A20 promotes prohibitin ubiquitination and degradation, leading to STAT3 activation and increased PD-L1 expression.
Conclusions:
- Tumorous A20 expression is linked to impaired antitumor immunity and resistance to anti-PD-1 immunotherapy in melanoma.
- Targeting A20 represents a novel strategy to enhance immunotherapy efficacy in refractory melanoma.
- A20 could serve as a promising biomarker and therapeutic target for melanoma patients.
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