Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

Tumor-associated macrophages (TAMs) play a role in tumor immune evasion and resistance to treatment. The specific epigenetic and transcriptional regulators that govern TAM function have been largely unknown. Researchers examined the impact of disrupting the SWI/SNF chromatin remodeling complex within TAMs to explore if this could enhance immunotherapy.

By inhibiting SWI/SNF ATPase activity pharmacologically, they observed that checkpoint blockade immunotherapy became more effective. Tumor growth slowed, and overall gene expression patterns shifted broadly in tumor cells, tumor-infiltrating lymphocytes, and TAMs. To focus on SWI/SNF's role in TAMs alone, they deleted the Arid1a subunit of SWI/SNF in myeloid cells, which proved sufficient to halt tumor progression and boost checkpoint blockade response.

Epigenomic and single-cell analyses showed that disrupting SWI/SNF and deleting ARID1A reduced enhancer accessibility at genes linked to negative outcomes, such as Spp1, while increasing accessibility at promoters of interferon-stimulated genes (ISGs). ARID1A-deficient TAMs displayed higher CD86 expression, and this enhancement of immunotherapy response hinged on CD86 costimulation and the involvement of CD8+ T cells.

These results solidify the importance of ARID1A-dependent chromatin remodeling in shaping TAM gene expression programs and demonstrate that tampering with myeloid SWI/SNF function can improve checkpoint blockade immunotherapy by reprogramming TAMs.