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Updated: Jun 5, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Exploring RPA1-ETAA1 axis via high-throughput data analysis: implications for PD-L1 nuclear translocation and
Gaofeng Qin1,2, Zengkuan Chen1,2, Weihong Tian1
1Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China.
Introduction:
ETAA1 is recruited to DNA damage sites via its RPA -binding and ATR -activating domain (AAD) motifs, where RPA binding is crucial for ETAA1's regulation of ATR activity.
Methods & Results:
Our findings associate Programmed Death- Ligand1 (PD-L1) with the RPA1-ETAA1 axis, suggesting that upregulated RPA1 -dependent ETAA1 may facilitate PD-L1 nuclear accumulation. We observed strong correlations between ETAA1 and RPA1 with the components involved in HDAC2-mediated deacetylation, clathrin -dependent endocytosis, and PD-L1 nucleocytoplasmic shuttling, aligning with the established regulatory pathway of PD-L1 nuclear translocation. Moreover, nuclear PD-L1 transactivates a panel of pro-inflammatory and immune response transcription factors, potentially reshaping the tumor immune microenvironment. We identified a landscape of infiltrating lymphocytes influenced by ETAA1, finding that levels of ETAA1 were negatively correlated with CD8+ T and Natural Killer T (NKT) cells, but positively correlated with CD4+ T helper 2 (Th2) cells, cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), neutrophils and regulatory T cells (Tregs), suggesting a potential role in immune evasion. Further analysis shows that the RPA1-ETAA1 axis is significantly associated with multiple metastasis mediators and unfavorable liver cancer progression, with higher expression observed in advanced stages and poorly differentiated subgroups.
Discussion & Conclusion:
These findings expand the role of the RPA1-ETAA1 axis beyond DNA repair, highlighting its potential as a target for cancer therapy.
Insights
The RPA1-ETAA1 axis, beyond DNA repair, influences Programmed Death-Ligand 1 (PD-L1) nuclear accumulation and reshapes the tumor immune microenvironment, indicating potential cancer therapy targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- The ETAA1 protein is recruited to DNA damage sites through its RPA-binding and ATR-activating domain (AAD) motifs.
- RPA binding is essential for ETAA1's regulation of ATR activity.
Purpose of the Study:
- To investigate the association of the RPA1-ETAA1 axis with Programmed Death-Ligand 1 (PD-L1) nuclear accumulation and its impact on the tumor immune microenvironment.
- To explore the role of the RPA1-ETAA1 axis in liver cancer progression and metastasis.
Main Methods:
- Correlation analysis between ETAA1, RPA1, and factors involved in PD-L1 nucleocytoplasmic shuttling.
- Analysis of immune cell infiltration and transcription factor activation.
- Assessment of RPA1-ETAA1 axis association with liver cancer stage and differentiation.
Main Results:
- The RPA1-ETAA1 axis is linked to PD-L1 nuclear accumulation via HDAC2-mediated deacetylation and clathrin-dependent endocytosis.
- Nuclear PD-L1 transactivates pro-inflammatory and immune response transcription factors.
- ETAA1 levels correlate with specific immune cell populations (e.g., decreased CD8+ T cells, increased Tregs) and are associated with advanced liver cancer stages and poor differentiation.
Conclusions:
- The RPA1-ETAA1 axis plays a role beyond DNA repair, influencing PD-L1 regulation and immune evasion.
- The RPA1-ETAA1 axis is associated with unfavorable liver cancer progression.
- The RPA1-ETAA1 axis represents a potential therapeutic target for cancer treatment.
