Abstract 4835: The role of ARID1A and ARID1B in melanoma
Authors: Pei-Yu Chen, George P. Souroullas
Journal: Cancer Research (2025)

Abstract ARID1A and ARID1B are highly homologous and mutually exclusive subunits of the chromatin remodeler SWI/SNF complex. In melanoma, ARID1A and ARID1B are mutated in about 13% and 10% of melanoma patients, respectively. Interestingly, mutations in ARID1A or ARID1B are also associated with a better response to immunotherapy in many cancers, highlighting their potential clinical relevance. The molecular mechanisms that drive this response, or their oncogenic mechanisms, remain largely unknown. What is also unknown are their unique and redundant properties within the SWI/SNF complex, and how that affects cancer progression. To study the function of ARID1A and ARID1B in melanoma, we crossed conditional knockout Arid1a and Arid1b mouse alleles to the tamoxifen-inducible tyrosinase Cre driver for melanocyte-specific deletion, in the presence of Braf V600E and Pten loss. We found that deletion of Arid1a or Arid1b did not change melanoma initiation; however, deletion of Arid1b accelerated nevi formation. Since melanoma initiation and progression can be two distinct processes, we next assessed the effect of Arid1a/1b deletion on melanoma progression. Using stable cell lines we generated from the primary tumors, we assessed melanoma tumor growth over time. We found that deletion of Arid1b dramatically decreased tumor growth compared to controls. Because deletion of Arid1a/1b did not affect in vitro cell growth, we hypothesized that cell extrinsic variables, like anti-tumor immunity, might be contributing to these phenotypes. Analysis of immune cell infiltration in the melanoma tumor revealed increased infiltration of CD8 T cells, particularly effector T cells in the absence of Arid1b, but not Arid1a. These results suggest that Arid1a and Arid1b are functionally distinct on regulating tumor immunity in melanoma.To mechanistically understand how Arid1a/1b affect melanoma progression, we performed gene expression profile analysis using RNA-seq. GSEA of RNA-seq data revealed enrichment in several immune-related signatures after Arid1b deletion, including IFN-α response, IFN-γ response, and MHC I antigen presentation and processing signatures. More specifically, we identified a dramatic upregulation of Stat1, an upstream regulator of MHC I antigen presentation genes that promote the cytotoxic activity of CD8 T cells. However, Stat1 remains largely unphosphorylated, so it remains unclear whether its upregulation results in increased canonical Stat signaling or whether it functions via other mechanisms. Overall, we show that Arid1a and Arid1b have distinct functions in a Braf/Pten-driven model of mouse melanoma and affect melanoma progression via alteration of pathways that control cytotoxic CD8 T cell activity. Finally, ARID1B may potentially serve as a predictive marker for immune checkpoint blockade treatment in melanoma patients. Citation Format: Pei-Yu Chen, George P. Souroullas. The role of ARID1A and ARID1B in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4835.