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Co-Expression of MHC-II and ANXA1: Mediators of PD-1/PD-L1 Therapy Resistance in Breast Cancer
Hao Wang1,2,3,4,5, Ji-Feng Sun1,5, Chen Wang1,2,3,4
1Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Background:
Triple-negative breast cancer (TNBC) presents significant treatment challenges and poor prognosis. While immune checkpoint blockade (ICB) therapy shows promise, patient responses vary widely, highlighting the urgent need for reliable biomarkers to predict efficacy and guide treatment decisions.
Aims:
This study aims to investigate the role of Major Histocompatibility Complex class II (MHC-II) expression in breast cancer, specifically focusing on its impact on immune evasion, tumor metastasis, and immunotherapy efficacy. The objective is to emphasize the necessity of targeted research in order to enhance therapeutic strategies for TNBC.
Methods:
We employed Limma for conducting differential expression analysis, clusterProfiler for performing GO and KEGG pathway enrichment analyses, and Mendelian randomization analyses utilizing data from the UK Biobank and GEO data sets. Single-cell sequencing data were analyzed using Scanpy and CellTypist, where UMAP, PCA, and the Leiden algorithm were applied to explore cellular heterogeneity as well as gene expression profiles.
Results:
We observed significant differential gene expression between MHC-II-high and MHC-II-low hematopoietic stem cells, which has an impact on immune responses and cancer pathways, particularly in TNBC. Mendelian randomization analysis identified key genes associated with breast cancer risk and PD-L1 status. Additionally, ANXA1 was significantly decreased in expression in breast cancer tissues compared to normal tissues and demonstrated increased expression in nonresponders to PD-1/PD-L1 therapies in TNBC patients, suggesting its potential involvement in immunotherapy resistance despite lacking a direct correlation with overall survival rates.
Conclusion:
The findings of this study highlight the potential role of ANXA1 in mediating resistance to PD-1/PD-L1 therapy in breast cancer, which is associated with MHC-II expression. ANXA1 could serve as both a predictive marker for treatment resistance and a therapeutic target to enhance the efficacy of immunotherapy.
Insights
This study reveals that ANXA1 may predict resistance to PD-1/PD-L1 immunotherapy in triple-negative breast cancer (TNBC). Targeting ANXA1 could improve treatment effectiveness for TNBC patients.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) poses significant treatment challenges with a poor prognosis.
- Immune checkpoint blockade (ICB) therapy shows variable patient responses, necessitating predictive biomarkers.
- Understanding mechanisms of immune evasion and treatment resistance is crucial for TNBC.
Purpose of the Study:
- To investigate the role of Major Histocompatibility Complex class II (MHC-II) expression in breast cancer.
- To assess MHC-II's impact on immune evasion, tumor metastasis, and immunotherapy efficacy.
- To identify potential therapeutic targets for enhancing TNBC treatment strategies.
Main Methods:
- Differential gene expression analysis using Limma.
- Gene Ontology (GO) and KEGG pathway enrichment analyses via clusterProfiler.
- Mendelian randomization analyses using UK Biobank and GEO datasets.
- Single-cell sequencing analysis with Scanpy and CellTypist, employing UMAP, PCA, and Leiden algorithm.
Main Results:
- Significant differential gene expression observed between MHC-II-high and MHC-II-low hematopoietic stem cells, impacting immune and cancer pathways in TNBC.
- Mendelian randomization identified key genes linked to breast cancer risk and PD-L1 status.
- ANXA1 expression was decreased in breast cancer tissues and increased in nonresponders to PD-1/PD-L1 therapy, suggesting a role in immunotherapy resistance.
Conclusions:
- ANXA1 may mediate resistance to PD-1/PD-L1 therapy in breast cancer, potentially linked to MHC-II expression.
- ANXA1 shows potential as a predictive marker for immunotherapy resistance in TNBC.
- Targeting ANXA1 could be a strategy to enhance immunotherapy efficacy in breast cancer treatment.
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