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Published on: September 12, 2019
CircSPECC1 attenuates sensitivity to PD-1 blockade through impaired antigen presentation in hepatocellular carcinoma
Rui Peng1, Jiahao Zhang1, Chi Zhang2
1Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital affiliated to Yangzhou University, No. 98 West Nantong Road, Yangzhou, Jiangsu, 225009, China.
Abstract:
Immune checkpoint inhibitors (ICIs) demonstrate therapeutic benefits in advanced hepatocellular carcinoma (HCC), yet most patients exhibit limited responses to anti-PD-1 therapy and the molecular basis underlying this resistance remains largely undefined. Here, we identified the circular RNA SPECC1 (circSPECC1) as a regulator of antigen presentation and a crucial factor influencing the efficacy of anti-PD-1 therapy. circSPECC1 was significantly elevated in tumor tissues of HCC patients showing resistance to anti-PD-1 therapy and correlated with diminished intratumoral CD8+ T-cell infiltration. Elevated circSPECC1 levels facilitated tumor progression and impaired the therapeutic efficacy of anti-PD-1 treatment. Overexpression of circSPECC1 in cancer cells suppressed the proliferation and cytotoxic activity of CD8+ T cells both in vitro and in vivo. Mechanistically, circSPECC1 bound to the peptide-loading complex (PLC) chaperone ERP57 and disrupted its interaction with TAPBP (TAP binding Protein), thereby destabilizing PLC integrity. This aberrant interaction redirected MHC-I toward ER-associated degradation (ERAD), suppressing surface antigen presentation and impairing CD8+ T-cell activation. Importantly, targeted silencing of circSPECC1 using a PEG-PEI-folate nanosystem encapsulating si-circSPECC1 significantly restored sensitivity both murine and patient-derived xenograft HCC models to PD-1 blockade. In summary, these findings uncover a novel circRNA-guided ERAD of MHC-I mechanism that impairs antitumor immunity and highlight circSPECC1 as a promising therapeutic target to overcome immunotherapy resistance.
Insights
Circular RNA SPECC1 (circSPECC1) drives resistance to anti-PD-1 immunotherapy in hepatocellular carcinoma (HCC) by impairing antigen presentation. Silencing circSPECC1 restores anti-tumor immunity and sensitivity to PD-1 blockade, offering a new therapeutic target.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) like anti-PD-1 therapy offer benefits in advanced hepatocellular carcinoma (HCC).
- However, many HCC patients show limited response to anti-PD-1 therapy, with the underlying resistance mechanisms poorly understood.
- Identifying novel targets is crucial to enhance immunotherapy efficacy in HCC.
Purpose of the Study:
- To identify molecular regulators of antigen presentation that influence anti-PD-1 therapy response in HCC.
- To elucidate the role of circular RNA SPECC1 (circSPECC1) in immunotherapy resistance.
- To explore circSPECC1 as a potential therapeutic target for overcoming resistance to PD-1 blockade in HCC.
Main Methods:
- Quantification of circSPECC1 levels in HCC tumor tissues.
- In vitro and in vivo experiments assessing the impact of circSPECC1 on CD8+ T cell activity.
- Mechanistic studies involving circSPECC1, ERP57, TAPBP, and the peptide-loading complex (PLC).
- In vivo evaluation of circSPECC1 silencing using a targeted nanosystem in HCC models.
Main Results:
- circSPECC1 was significantly elevated in HCC patients resistant to anti-PD-1 therapy.
- Elevated circSPECC1 suppressed intratumoral CD8+ T cell infiltration, proliferation, and cytotoxic activity.
- circSPECC1 disrupts the peptide-loading complex by interacting with ERP57, leading to MHC-I degradation and reduced antigen presentation.
- Targeted silencing of circSPECC1 restored sensitivity to anti-PD-1 therapy in preclinical HCC models.
Conclusions:
- circSPECC1 acts as a key regulator of antigen presentation and a driver of resistance to anti-PD-1 therapy in HCC.
- The study uncovers a novel circRNA-mediated ER-associated degradation of MHC-I pathway impairing anti-tumor immunity.
- circSPECC1 represents a promising therapeutic target to enhance the efficacy of immunotherapy in HCC.
