Impact of Mutations in Subunit Genes of the Mammalian SWI/SNF Complex on Immunological Tumor Microenvironment

Abstract

Background/Aim: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. Patients and Methods: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. Results: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell

Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go

“…The biological mechanisms driving the antitumor activity of ICIs in SMARCA4-UT are not yet understood; abnormalities in the SWI/SNF complex correlate with enhanced interferon-gamma-induced T-cell cytotoxicity and better outcomes concerning ICIs in other malignancies [ 77 , 78 ] An enriched Th1 and cytotoxic T-cell microenvironment was recently reported in four cases of SMARCA4-deficient SCCOHT with prolonged responses to ICIs [ 77 ]. To the best of our knowledge, only one study has reported a low response rate to ICIs in SMARCA4-UT, which was associated with an absence of tumor-infiltrating lymphocytes in the TME [ 79 ] Conversely, Hozumi et al [ 80 ] showed that low SMARCA4 expression correlates with the upregulation of the T cell effector; the mature B cell marker; and central memory marker genes, such as CD8B, CD40LG, CD20, CD38, CD79, interferon Regulatory Factor 4, CD27, and -C motif chemokine receptor 7. At the same time, chemokines that attract functional T and B cells inside tumors (namely, chemokine (C-C motif) ligand (CCL)19 and CCL21) are upregulated, while chemokines that induce an immunosuppressive TME (namely, Interleukin 20 receptor, alpha subunit, CD200, and CXCL8) are downregulated in patients with cancer harboring low SMARCA4 expression.…”

“…At the same time, chemokines that attract functional T and B cells inside tumors (namely, chemokine (C-C motif) ligand (CCL)19 and CCL21) are upregulated, while chemokines that induce an immunosuppressive TME (namely, Interleukin 20 receptor, alpha subunit, CD200, and CXCL8) are downregulated in patients with cancer harboring low SMARCA4 expression. Overall, low SMARCA4 expression correlates with an upregulated tertiary lymphoid structure (TLS)-associated gene signature, suggesting that the development of mature B cell accumulation in SMARCA4-deficient tumors is a potential mechanism of immune checkpoint-based therapy sensitivity [ 80 ].…”