Immune Circuit Rewiring by HDAC Inhibition Enables Response to Dual Checkpoint Blockade in Metastatic Breast Cancer

Area of Science:

• Immunology
• Oncology
• Computational Biology

Background:

• Metastatic breast cancer often exhibits immune suppression, necessitating novel immunotherapeutic strategies.
• Histone deacetylase (HDAC) inhibitors show potential in sensitizing tumors to dual immune checkpoint inhibitors.
• Understanding the tumor microenvironment (TME) is key to optimizing combination therapies.

Purpose of the Study:

• To elucidate the mechanisms of response to combined entinostat (HDAC inhibitor) with anti-PD-1 and anti-CTLA-4 in metastatic breast cancer.
• To investigate the impact of this combination therapy on the TME using integrated experimental and computational approaches.
• To identify key cellular players and pathways involved in treatment efficacy.

Main Methods:

• Single-cell RNA-sequencing (scRNA-seq) and cell circuit analysis in murine breast-to-lung metastases.
• Spatial proteomics and flow cytometry on patient biopsies and blood samples.
• Mathematical modeling of tumor-immune dynamics.

Main Results:

• Identified 39 cell states, with myeloid, T cells, and B cells significantly affected by combination treatment.
• Observed increased T cell and B cell activation, mature tertiary lymphoid structures, and altered CD8+ T cell-macrophage interactions in responders.
• Demonstrated increased immunoglobulin production and highlighted B cells as essential for treatment response in murine models.

Conclusions:

• HDAC inhibitors combined with dual immune checkpoint blockade reprogram the TME, enhancing anti-tumor immunity.
• Lymphoid and myeloid cell modulation, particularly B cell activation and immunoglobulin production, are critical for response.
• This study provides a framework for understanding complex TME interactions and developing targeted immunotherapies for breast cancer.