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Published on: May 17, 2019
EGC enhances tumor antigen presentation and CD8+ T cell-mediated antitumor immunity via targeting oncoprotein SND1
Xinxin Zhang1, Xiaoteng Cui2, Peiying Li1
1Tianjin Key Laboratory of Cellular and Molecular Immunology, and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China; State Key Laboratory of Experimental Hematology, Tianjin, China; Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China.
Abstract:
The Staphylococcal nuclease and Tudor domain containing 1 (SND1) has been identified as an oncoprotein. Our previous study demonstrated that SND1 impedes the major histocompatibility complex class I (MHC-I) assembly by hijacking the nascent heavy chain of MHC-I to endoplasmic reticulum-associated degradation. Herein, we aimed to identify inhibitors to block SND1-MHC-I binding, to facilitate the MHC-I presentation and tumor immunotherapy. Our findings validated the importance of the K490-containing sites in SND1-MHC-I complex. Through structure-based virtual screening and docking analysis, (-)-Epigallocatechin (EGC) exhibited the highest docking score to prevent the binding of MHC-I to SND1 by altering the spatial conformation of SND1. Additionally, EGC treatment resulted in increased expression levels of membrane-presented MHC-I in tumor cells. The C57BL/6J murine orthotopic melanoma model validated that EGC increases infiltration and activity of CD8+ T cells in both the tumor and spleen. Furthermore, the combination of EGC with programmed death-1 (PD-1) antibody demonstrated a superior antitumor effect. In summary, we identified EGC as a novel inhibitor of SND1-MHC-I interaction, prompting MHC-I presentation to improve CD8+ T cell response within the tumor microenvironment. This discovery presents a promising immunotherapeutic candidate for tumors.
Insights
We identified (-)-Epigallocatechin (EGC) as a novel inhibitor that blocks the oncoprotein SND1 from binding to MHC-I. This enhances tumor immunotherapy by improving T cell responses against cancer.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an oncoprotein that hinders major histocompatibility complex class I (MHC-I) presentation.
- SND1 targets MHC-I heavy chains for degradation, reducing cancer cells' ability to display antigens.
Purpose of the Study:
- To identify inhibitors that disrupt the SND1-MHC-I interaction.
- To enhance MHC-I presentation for improved tumor immunotherapy.
Main Methods:
- Structure-based virtual screening and docking analysis identified potential inhibitors.
- In vitro assays assessed the effect of inhibitors on MHC-I expression.
- Murine melanoma models evaluated anti-tumor efficacy and T cell responses.
- Combination therapy with PD-1 antibody was tested.
Main Results:
- (-)-Epigallocatechin (EGC) showed high binding affinity, preventing SND1-MHC-I interaction by altering SND1 conformation.
- EGC treatment increased membrane-bound MHC-I expression in tumor cells.
- EGC enhanced CD8+ T cell infiltration and activity in tumors and spleens.
- Combined EGC and PD-1 antibody treatment yielded superior anti-tumor effects.
Conclusions:
- EGC is a novel inhibitor of the SND1-MHC-I interaction.
- EGC enhances MHC-I presentation, boosting CD8+ T cell responses.
- EGC represents a promising immunotherapeutic candidate for cancer treatment.
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