Inhibitors of the BAF nucleosome remodeling 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.
BAF inhibitors (FHD-286 or BRM014) dramatically increased the response of MC38 adenocarcinoma tumors to anti-PD-L1 immunotherapy. Multiplexed 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, T cells and macrophages. Tumor associated macrophages (TAMs) displayed increased expression of antigen presentation (MHC-I) and co-stimulation (CD86) transcripts and proteins, identifying the previously unrecognized possibility that targeting the BAF complex could re-program TAMs from immune-suppressive cells that promote tumor growth to cells that can boost the anti-tumor response.
To specifically study the role of BAF in TAMs, we used a mouse model with myeloid-specific deletion of ARID1A (the largest subunit of the canonical BAF complex). Tumor growth was slowed in this model and the response to anti-PD-L1 was boosted, phenocopying effects observed with BAF-complex inhibitors. ARID1A-deleted TAMs displayed widespread changes in gene expression and chromatin accessibility. Several thousand enhancers became inaccessible, consistent with a direct role for the ARID1A-containing-BAF complex in opening enhancer chromatin. Additionally, accessibility increased at several thousand sites following ARID1A loss, including at promoters of ISGs that were upregulated transcriptionally. Specific ISGs were hyperinduced by the addition of interferon, however were already increased in a cell-intrinsic manner at baseline, independent of IFNAR and JAK1/2 signaling. This suggests an epigenetic mechanism boosting basal ISG expression in the absence of ARID1A, likely mediated by compensatory factors. We showed that the ISG, CD86, was functionally important in the observed tumor control, linking the molecular changes to a cellular mechanism.