The BAF complex is a multi-subunit nucleosome-remodeling complex. Inhibitors of the BAF complex have entered phase I clinical trials due to the dependency of several cancer types on the BAF complex. We hypothesized that BAF complex inhibitors would impact not only tumor cells directly, but also affect cells of the tumor microenvironment.
Subcutaneous growth of MC38 adenocarcinoma was substantially slowed in mice treated with BAF inhibitors (FHD-286 or BRM014) and anti-PD-L1 compared to mice treated with PD-L1 alone. Multiome scRNA and scATAC sequencing revealed changes in the gene expression and chromatin accessibility across several cell types, including upregulation of interferon signature genes (ISGs) in tumor cells, CD8+ T cells and macrophages. Tumor associated macrophages (TAMs) displayed reduced expression of CD206, associated with immunosuppression, and increased expression of antigen presentation (MHC-I) and co-stimulation (CD86) proteins, identifying a previously unrecognized role of the BAF complex in TAM function.
To directly study the role of BAF in TAMs, we used a mouse model with myeloid-specific (LysM-Cre and Itgax-Cre) deletion of ARID1A (the largest subunit of the canonical BAF complex). Growth of tumor lines was slowed in mice lacking myeloid-ARID1A compared to controls and the response to anti-PD-L1 was boosted, phenocopying effects observed with BAF-complex inhibitors. ARID1A-deleted TAMs displayed widespread changes in chromatin accessibility and gene expression, including an enrichment of ISGs. Upregulated ISGs with increased promoter accessibility included the gene-encoding the co-stimulatory CD86 molecule, known to be important for activation of T cells by antigen-presenting cells. In vitro experiments established that the upregulation of Cd86 in ARID1A-deficient macrophages was not dependent on soluble factors, but could be hyperinduced by interferon or co-culture with T cells. In vivo, cells lacking myeloid-specific ARID1A showed increased CD8+ T cell activation. Using depleting and blocking antibodies respectively, we established the tumor growth phenotype was dependent on CD8+ T cells, and partly dependent on CD86, highlighting the role of TAM:CD8+ T cell cross talk in promoting an anti-tumor immune response.
Collectively, we discovered the BAF complex is a regulator of tumor-associated macrophages and identified a molecular and cellular mechanism through which myeloid-specific ARID1A-loss boosts anti-tumor immunity.