Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 141, Issue 6, Pages 1564-+Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2020.11.026
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Funding
- Japan Society for Promotion of Science KAKENHI [JP20309138]
- Okinaka Memorial Institute for Medical Research
- Japanese Association of Geriatric Dermatology
- Health and Labor Science, Japan
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The study demonstrates that ARID2 knockout enhances melanoma sensitivity to immune checkpoint inhibitors by increasing infiltration of cytotoxic CD8(+) T cells and upregulating expression of T-cell-attracting chemokines. These findings suggest that ARID2 acts as an immunomodulator and a potential biomarker for predicting the effectiveness of immune checkpoint inhibitors in melanoma patients.
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 evi-dence 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 im-mune 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.
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