Regulation of IL-4 macrophage polarization by SWI/SNF family complexes

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Project Summary/Abstract Macrophage polarization into activated M1 (inflammatory) and M2 (immunosuppressive) subsets is critical to immune function. The failure to properly regulate polarization can lead to chronic inflammation, autoimmunity, and cancer progression. In malignancy, the polarization of immunosuppressive tumor-associated macrophages (TAMs) is a strong predictor of prognosis for many solid tumors and has been a significant hurdle to immunotherapies designed to activate strong anti-cancer T cell responses, including immune checkpoint blockade (ICB) and CAR-T cell therapies. Macrophage polarization is driven by signal-induced STAT transcription factors, which cooperate with SWI/SNF-family ATP-dependent chromatin remodeling complexes to alter DNA accessibility and to create sustained gene expression changes. In preliminary studies, I have found that SWI/SNF activity is critical to M2 macrophage polarization, and we believe this dependency has the potential to be therapeutically targeted to prevent immunosuppressive TAM accumulation in solid tumors. We hypothesize that SWI/SNF-family chromatin remodelers (BAF/PBAF/GBAF) are critical to the acquisition of immunosuppressive macrophage phenotypes and play differential roles in generating chromatin accessibility during polarization by IL-4. We expect that these remodelers enable gene activation by generating DNA accessibility across the genome for polarization-induced STAT TF binding sites. To address this central hypothesis, we will inhibit SWI/SNF activity, then identify the SWI/SNF dependencies of IL-4 induced M2 polarization via functional, transcriptomic, and epigenomic profiling. We will also validate the role of SWI/SNF inhibition on the tumor microenvironment in an immunocompetent mouse model of cancer. Through this proposal, we aim to leverage the contribution of SWI/SNF chromatin remodelers to control TAM phenotypes in cancer. Understanding the epigenetic features that regulate M2 polarization will provide opportunities to improve patient outcomes by reducing the anti-inflammatory polarization phenotypes of TAMs. As a result, our work has the potential to help turn immunologically “cold” tumors “hot.”