SOX10 Inhibits T Cell Recognition by Inducing Expression of the Immune Checkpoint Molecule PD-L1 in A375 Melanoma Cells

Sasaki, Kenta; Hirohashi, Yoshihiko; Murata, Kenji; Minowa, Tomoyuki; Nakatsugawa, Munehide; Murai, Aiko; Mizue, Yuka; Kubo, Terufumi; Kanaseki, Takayuki; Tsukahara, Tomohide; Iwabuchi, Sadahiro; Hashimoto, Shinichi; Uhara, Hisashi; Ishida‐Yamamoto, Akemi; Torigoe, Toshihiko

doi:10.21873/anticanres.16296

Cited by 4 publications

(3 citation statements)

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“…SOX10 is a neural crest lineage-specific transcription factor that regulates melanoma development, rapid tumor growth and tumor immunogenicity. [4][5][6][7][8][9][10][11][12] Additionally, SOX10 has been shown to play a crucial role in melanoma phenotype switching through repression of a metastatic transcriptional program. 13 Efforts to therapeutically target SOX10 have been challenging due to the relative inaccessibility of targeted therapies to transcription factors and specific complexities associated with loss of SOX10 activity, which may promote tumor cell invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 SOX10 is a neural crest lineage-specific transcription factor that is highly expressed in the melanocytic, transitory and neural crest-like melanoma phenotypes 4 and is essential for melanoma development [5][6][7] , rapid growth 5,7,8 , and regulation of tumor immunogenicity. [9][10][11][12] Loss of SOX10 induces an undifferentiated melanoma phenotype characterized by slow-growth, increased metastatic potential and MAPK-inhibitor (MAPKi) resistance. 8,13 While key regulators of SOX10 function are under intense investigation and may serve as potential therapeutic strategies to target SOX10 tumorigenic activity in melanoma [14][15][16][17][18][19][20][21][22][23][24][25] , such studies have failed to yield meaningful progress to date.…”

Section: Introductionmentioning

confidence: 99%

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p300 KAT regulates SOX10 stability and function in human melanoma

Waddell,

Grbic,

Leibowitz

et al. 2024

Preprint

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SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in melanoma proliferation, while preventing a concomitant increase in tumor cell invasion. Here, we report that the lysine acetyltransferase (KAT)EP300andSOX10gene loci on Chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor, A-485, downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlowmelanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion, and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

p300 KAT regulates SOX10 stability and function in human melanoma

Waddell,

Grbic,

Leibowitz

et al. 2024

Preprint

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show abstract

“…As reported in few studies PD-L1 expression in ONB samples was found to be poor, which translates into a lower chance of response to anti-PD-1/PD-L1 drugs (12), consisted with previous studies, in our study only one (1/15) case expressed PD-L1 (combined positive score (CPS) ≥ 1) in the tumor region. When compared with non-small cell lung cancer and skin melanoma, cancer types in which immunotherapy has shown good response (34,35), ONB samples had significantly less upregulation of PD-L1. The results of TMB, PD-L1, and CD8 + Tils suggest that ONB may be insensitive to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling and immune landscape of olfactory neuroblastoma in China

Yang,

Wan,

Zhang

et al. 2023

Front. Oncol.

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BackgroundOlfactory neuroblastoma (ONB) is a rare malignant neoplasm of the olfactory mucosa. The paucity of genomic data has prevented the development of individualized ONB treatments. Here, we investigated the genomic and immune landscape of ONB in Chinese patients.MethodsWhole exome sequencing (WES) and multiplex immunofluorescence (MIF) analysis were performed on tissue samples from 19 Chinese ONB patients. Patients were divided into low- and high-grade groups.ResultsOverall, 929 nonsynonymous alterations were identified in 18 (94.74%) ONB cases. The most prevalent altered cancer-related genes were CTNNB1 (16%) and ZNRF3 (16%). The most mutated oncogenic pathways were the WNT and RAS pathways. The median tumor mutation burden (TMB) was 0.45, ranging from 0 to 3.25. Only one case expressed PD-L1 (> 1%) in the tumor region. The percentage of CD8+ tumor-infiltrating lymphocytes (TILs) in the tumor region ranged from 0.03% to 84.9%, with a median of 1.08%. No significant differences were observed between the low- and high-grade groups for clinicopathological features, mutant genes, mutant pathways, TMB, tumor neoantigen burden (TNB), mutant-allele tumor heterogeneity (MATH), PD-L1 expression levels, or CD8+ TIL percentage. However, the low-grade group showed significantly more CD68+ macrophages in both the tumor and total region than the high-grade group. Notably, CD68+CD163- macrophages accounted for an average of 80.5% of CD68+ macrophages.ConclusionThis study presents data on the genomic and immune landscape of ONB cases in China. CTNNB1 and ZNRF3 were the most prevalent altered cancer-related genes. The results of TMB, PD-L1, and CD8+ Tils suggest that ONB may be insensitive to immunotherapy. M1 macrophages may be positively associated with the prognosis of ONB.Implications for PracticeIn this study, the most prevalent altered cancer-related genes were CTNNB1 (16%) and ZNRF3 (16%). The most mutated oncogenic pathways were the WNT and RAS pathways. The median tumor mutation burden (TMB) was 0.45, ranging from 0 to 3.25. Only one (1/15) case expressed PD-L1 (> 1%) in the tumor region. However, the low-grade group showed significantly more CD68+ macrophages in both the tumor and total region than the high-grade group. The higher level of CD68-related macrophages indicates that M1 macrophages potentially play an important role in ONB development that is possibly associated with prognosis.

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p300 KAT Regulates SOX10 Stability and Function in Human Melanoma

Waddell,

Grbic,

Leibowitz

et al. 2024

Cancer Research Communications

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SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in melanoma proliferation, while preventing a concomitant increase in tumor cell invasion. Here, we report that the lysine acetyltransferase (KAT) EP300 and SOX10 gene loci on Chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor, A-485, downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlow melanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion, and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.

show abstract

SOX10 Inhibits T Cell Recognition by Inducing Expression of the Immune Checkpoint Molecule PD-L1 in A375 Melanoma Cells

Cited by 4 publications

References 0 publications

p300 KAT regulates SOX10 stability and function in human melanoma

p300 KAT regulates SOX10 stability and function in human melanoma

Genomic profiling and immune landscape of olfactory neuroblastoma in China

p300 KAT Regulates SOX10 Stability and Function in Human Melanoma

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