Abstract P95: PDCD11, Enriched in Cancer cell-Derived Extracellular Vesicles, Promotes Immunosuppressive Macrophage Polarization and Tumor Immune Evasion in HBV related Hepatocellular Carcinoma
Indrashish Dey, Debalina Mukherjee, Arittri Bhowmick, Simanti Datta, Abhijit Chowdhury, Soma BanerjeeAbstract
Background:
Chronic hepatitis B is the main cause of hepatocellular carcinoma (HCC) increasing worldwide. In addition to liver residing cells, the infiltrating immune cells in the tumor microenvironment (TME) promotes initiation, progression, and metastasis of HCC. Within the TME, extracellular vesicles (EVs)-derived cargos from various cells play an important role in cell-cell communication.
Aim:
This study examined the impact of cancer cell-derived EVs on the functional plasticity of macrophages, one of the abundant innate immune cells, and its effects on the TME.
Methods:
Huh7/HepG2/HepG2.2.15 (HBV-stable cells)/THP1 cell lines were used. EVs/EV-enriched proteins were isolated from HepG2-vector/HepG2.2.15 using kit, and performed liquid chromatography-mass spectrometry (LC-MS). PLGS tool/UniProtKB/Swiss-Prot server/DAVID used for data analysis/BIOGRID for protein-protein interaction. Single cell transcriptome (ScT)/Survival analysis/transfection/qRT-PCR/Co-culture/Immunoblotting/FACS/confocal microscopy/anti-sense oligo (ASO)/EV-inhibitor treatment were conducted. SPSS/GraphPad Prism were used for Statistical analysis.
Results:
The proteome analysis of EVs-derived from HepG2.2.15 cells and HepG2-control cells revealed PDCD11 as one of the enriched RNA-binding protein in HepG2.2.15, but this protein was not intracellularly overexpressed. BIOGRID interaction analysis and in In vitro validation using ASO and co-immunoprecipitation demonstrated that ANLN directly interacts with PDCD11 to facilitate its selective loading into EVs. ANLN expression was found to be upregulated by HBx, but since it lacks DNA-binding domain, promoter analysis and ChIP showed that the HBx/E2F1 complex transactivated ANLN. Subsequently, PDCD11-ANLN-enriched EVs, when incubated with PMA-treated THP-1 cells, induced M2 polarization. PDCD11 promoted the NF-κB-cREL-MYC signaling axis in macrophages. It stabilized GARIN4 and delayed fragmentation of the Golgi apparatus, resulting in the expression of the immunosuppressive marker PD-L1 in PMA-treated THP-1 cells, as demonstrated through confocal microscopy/qRT-PCR, and flow cytometry analysis.
Conclusions:
This study highlights the role of PDCD11 in promoting macrophages toward a pro-tumorigenic state, suggesting that PDCD11 could have therapeutic potential alongside immunotherapy and can be used for clinical management of HBV-HCC patient.
Citation Format:
Indrashish Dey, Debalina Mukherjee, Arittri Bhowmick, Simanti Datta, Abhijit Chowdhury, Soma Banerjee. PDCD11, Enriched in Cancer cell-Derived Extracellular Vesicles, Promotes Immunosuppressive Macrophage Polarization and Tumor Immune Evasion in HBV related Hepatocellular Carcinoma [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P95.