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Efferocytosis and M2 Macrophage Polarization Gene Expression Correlates With Relapsed and Refractory Classical
Juan Quarroz Braghini1, María Cecilia Cabral Lorenzo1, Laura Kornblihtt2
1División Anatomía Patológica, Facultad de Medicina, Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, Buenos Aires, Argentina.
Insights
A new gene signature accurately identifies Hodgkin-Reed Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL). HRS cells and M2 macrophages predict treatment failure, highlighting efferocytosis as a potential therapeutic target in cHL.
Area of Science:
- Hematology
- Immunology
- Genomics
Background:
- Classical Hodgkin Lymphoma (cHL) is characterized by rare malignant Hodgkin-Reed Sternberg (HRS) cells within an immune-rich microenvironment.
- Understanding the interactions between HRS cells and the immune microenvironment is crucial for predicting treatment response.
Purpose of the Study:
- To develop and validate a gene expression signature for identifying HRS cells in single-cell RNA sequencing (scRNA-seq) data.
- To investigate cell-cell interactions and analyze bulk transcriptomes to identify predictors of treatment failure in cHL.
- To assess the role of HRS cells and immune cell infiltration in treatment response.
Main Methods:
- Development of a 37-gene HRS cell signature.
- Processing of scRNA-seq data for cell type annotation and interaction analysis (CellPhoneDB).
- Bulk transcriptome deconvolution (CIBERSORT) and ridge regression modeling for predicting response to treatment (RtoT).
Main Results:
- The HRS cell signature accurately identified HRS cells (2.7%) in scRNA-seq data, with enrichment of the efferocytosis pathway.
- Macrophages, particularly M2 macrophages, showed significant cognate interactions with HRS cells, including efferocytosis.
- Increased M2 macrophage proportions and specific gene expression (MerTK, CD209, CD14, CD36) correlated with poorer RtoT (AUC 0.83, combined AUC 0.87).
Conclusions:
- A validated HRS cell gene signature enables precise identification and quantification of HRS cells.
- HRS cell and M2 macrophage proportions, along with efferocytosis-related genes, are significant predictors of treatment failure in cHL.
- Efferocytosis-mediated M2 macrophage polarization, influenced by HRS cells, represents a critical immune checkpoint in cHL, suggesting potential therapeutic avenues.
Abstract:
Classical Hodgkin Lymphoma (cHL) exhibits rare malignant Hodgkin-Reed Sternberg (HRS) cells within a reactive immune microenvironment. This study developed an HRS cell gene expression signature to identify HRS cells in single-cell RNA sequencing (scRNA-seq) data, investigated cognate interactions, analyzed bulk transcriptomes, and assessed predictors of treatment failure. Differentially expressed genes (DEGs) from RelB-silenced U-HO1 cells were identified, and scRNA-seq data was processed to annotate cell types. Cognate interactions were analyzed using CellPhoneDB, and bulk transcriptome deconvolution was performed using CIBERSORT. Ridge regression models were built and evaluated. A 37-gene HRS cell signature identified HRS cells (2.7%) in scRNA-seq data, revealing efferocytosis pathway enrichment. Macrophages showed the highest cognate interactions, including efferocytosis-related interactions with HRS cells. Bulk transcriptome analysis of 130 cHL patients showed increased M2 macrophage proportions correlated with poorer treatment response (p < 0.001). Ridge regression predicted response to treatment (RtoT) with an AUC of 0.83, identifying HRS cells and M2 macrophages as key predictors. Hierarchical clustering based on 19 genes revealed distinct RtoT outcomes, with high efferocytosis/M2 gene expression correlating with poor response. Increased MerTK, CD209, CD14, and CD36 expression was associated with poorer outcomes. Combining gene expression and cell type proportions improved RtoT prediction (AUC 0.87). A validated HRS cell gene expression signature enabled precise HRS cell identification and accurate estimation of cell proportions. HRS cell and M2 macrophage proportions, along with efferocytosis-related genes, predicted treatment failure. Efferocytosis-mediated M2 macrophage polarization, controlled by HRS cells, may be a critical immune checkpoint in cHL.
