Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, Kobe, Japan; Immunology, Microenvironment and Metastasis Program, Cancer Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Immunology, Microenvironment and Metastasis Program, Cancer Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
J Invest Dermatol. 2021 Jun;141(6):1564-1572.e4. doi: 10.1016/j.jid.2020.11.026. Epub 2020 Dec 15.
The SWI/SNF chromatin remodeler family includes the BAF and PBAF complexes. ARID2, encoding a PBAF complex subunit, is frequently mutated in melanoma independently of BRAF/RAS mutations. Emerging evidence shows that SWI/SNF complexes regulate tumor immunity; for instance, the loss of PBRM1, another PBAF complex subunit, enhances susceptibility to immune checkpoint inhibitors in melanoma. Notably, ARID2 mutations are more frequent in melanoma than PBRM1 mutations. However, the role of ARID2 as a modulator of tumor immunity remains unclear. In this study, we show that ARID2 knockout sensitizes melanoma to immune checkpoint inhibitors. Anti‒PD-L1 treatment restricts tumor growth in mice bearing ARID2-knockout melanoma cells, correlating with an increase in the infiltration of cytotoxic CD8 T cells. Furthermore, ARID2 deficiency leads to signal transducer and activator of transcription 1 upregulation, which subsequently causes increased expression of T-cell‒attracting chemokines such as CXCL9, CXCL10, and CCL5. These results demonstrate that ARID2 is an immunomodulator and a potential biomarker that indicates immune checkpoint inhibitor effectiveness in patients with melanoma.
SWI/SNF 染色质重塑酶家族包括 BAF 和 PBAF 复合物。编码 PBAF 复合物亚基的 ARID2 在黑色素瘤中经常发生突变，与 BRAF/RAS 突变无关。新出现的证据表明，SWI/SNF 复合物调节肿瘤免疫；例如，另一个 PBAF 复合物亚基 PBRM1 的缺失增强了黑色素瘤对免疫检查点抑制剂的敏感性。值得注意的是，ARID2 突变在黑色素瘤中的频率高于 PBRM1 突变。然而，ARID2 作为肿瘤免疫调节剂的作用尚不清楚。在这项研究中，我们表明 ARID2 敲除使黑色素瘤对免疫检查点抑制剂敏感。抗 PD-L1 治疗限制了携带 ARID2 敲除黑色素瘤细胞的小鼠的肿瘤生长，与细胞毒性 CD8 T 细胞浸润增加相关。此外，ARID2 缺陷导致信号转导和转录激活因子 1 的上调，随后导致吸引 T 细胞的趋化因子如 CXCL9、CXCL10 和 CCL5 的表达增加。这些结果表明 ARID2 是一种免疫调节剂和潜在的生物标志物，表明免疫检查点抑制剂对黑色素瘤患者的有效性。
