IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

Dibra, Denada; Mitra, Abhisek; Newman, Melissa; Xia, Xueqing; Keenan, Camille; Cutrera, Jeffry J.; Mathis, J. Michael; Wang, Xiao Jing; Myers, Jeffrey N.; Li, Shulin

doi:10.18632/oncotarget.12581

Cited by 4 publications

(4 citation statements)

References 53 publications

(67 reference statements)

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“…The following antibodies were used: primary antibody against PD-L1 (Proteintech 17952 and 66248, GeneTex GTX31308), pan-AKT (Cell Signaling Technology 4685), phosphor-AKT S473 (Abcam ab81283, Cell Signaling Technology 9271), GSK3β (Cell Signaling Technology 12456), phosphor-GSK3β Ser9 (Cell Signaling Technology 5558), WSX1 (Thermo Fisher PA5-96963), β-catenin (Cell Signaling Technology 8480), phosphor-β-catenin Ser33/37/Thr41 (Cell Signaling Technology 9561), PTEN (Cell Signaling Technology 9188), phospho-TSC2 Thr1462 (Cell Signaling Technology 3617), TSC2 (Cell Signaling Technology 4308), PI3K-p85 (Cell Signaling Technology 4292), PI3K-p110α (Cell Signaling Technology 4255), PI3K-p110δ (Cell Signaling Technology 34050), FLAG (Cell Signaling Technology 2368), Ub (Santa Cruz Biotechnology sc-8017), and WSX1 (clone 237, Monoclonal Antibodies Core Facility at MD Anderson Cancer Center) 74 . PerCP/Cyanine5.5 anti-mouse CD3 (BioLegend 100328), V450 anti-mouse CD8a (Tonbo 75-0081), FITC anti-mouse CD4 (BioLegend 100405), V450 anti-mouse NK1.1 (BD biosciences 560524), PE/Cy7 anti-mouse PD-1 (BioLegend 109109), PE anti-mouse CTLA-4 (BioLegend 106306), PE/Cy7 anti-mouse LAG-3 (BioLegend 125225), PE anti-mouse Tim3 (BioLegend 134009), PE anti-mouse granzyme B (ebioscience 12-8898-80), PE anti-mouse Ki67 (BioLegend 652404), PE anti-mouse perforin (ebioscience 12-9392-82), PE anti-human CD3 (BioLegend 300308), PE/Cy7 anti-human PD-1 (BioLegend 367414), APC anti-mouse TOX (Miltenyi Biotec 130-118-335), APC anti-mouse IFN-γ (ebioscience 17-7311-82), PE anti-mouse IL-2 (BioLegend 503808), PE anti-human WSX1 (R&D FAB14791P), and HRP anti-human/mouse GAPDH (Proteintech HRP-6000).…”

Section: Methodsmentioning

confidence: 99%

WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression

Xia

et al. 2021

Nat Commun

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WSX1, a receptor subunit for IL-27, is widely expressed in immune cells and closely involved in immune response, but its function in nonimmune cells remains unknown. Here we report that WSX1 is highly expressed in human hepatocytes but downregulated in hepatocellular carcinoma (HCC) cells. Using NRAS/AKT-derived spontaneous HCC mouse models, we reveal an IL-27–independent tumor-suppressive effect of WSX1 that largely relies on CD8+ T-cell immune surveillance via reducing neoplastic PD-L1 expression and the associated CD8+ T-cell exhaustion. Mechanistically, WSX1 transcriptionally downregulates an isoform of PI3K—PI3Kδ and thereby inactivates AKT, reducing AKT-induced GSK3β inhibition. Activated GSK3β then boosts PD-L1 degradation, resulting in PD-L1 reduction. Overall, we demonstrate that WSX1 is a tumor suppressor that reinforces hepatic immune surveillance by blocking the PI3Kδ/AKT/GSK3β/PD-L1 pathway. Our results may yield insights into the host homeostatic control of immune response and benefit the development of cancer immunotherapies.

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Section: Methodsmentioning

confidence: 99%

WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression

Xia

et al. 2021

Nat Commun

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“…IL-27 induced CD11b cells with endothelin A receptor (ETAR)-positive phenotype. Thus, in SCC patients, Dibra et al showed that IL-27RA-positive cells in the tumor stroma are correlated with tumor de-differentiation (69).…”

Section: Non-melanoma Tumors: Squamous Cell and Basal Cell Skin Carcimentioning

confidence: 99%

Inflammation: A key process in skin tumorigenesis (Review)

et al. 2018

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The extremely delicate shift from an inflammatory process to tumorigenesis is a field of major scientific interest. While the inflammation induced by environmental agents has well known underlying mechanisms, less is known concerning the oncogenic changes that follow an inflammatory chronic status in the tissue microenvironment that can lead to pro-tumorigenic processes. Regardless of the origin of the environmental factors, the maintenance of an inflammatory microenvironment is a clear condition that favors tumorigenesis. Inflammation sustains the proliferation and survival of malignant transformed cells, can promote angiogenesis and metastatic processes, can negatively regulate the antitumoral adaptive and innate immune responses and may alter the efficacy of therapeutic agents. There is an abundance of studies focusing on molecular pathways that trigger inflammation-mediated tumorigenesis, and these data have revealed a series of biomarkers that can improve the diagnosis and prognosis in oncology. In skin there is a clear connection between tissue destruction, inflammation and tumor onset. Inflammation is a self-limiting process in normal physiological conditions, while tumor is a constitutive process activating new pro-tumor mechanisms. Among skin cancers, the most commonly diagnosed skin cancers, squamous cell carcinoma and basal cell carcinoma (BCC) have important inflammatory components. The most aggressive skin cancer, melanoma, is extensively research in regards to the new context of novel developed immune-therapies. In skin cancers, inflammatory markers can find their place in the biomarker set for improvement of diagnosis and prognosis.

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“…In a previous research conducted by Dibra et al [ 27 ], IL-27 was shown to play an unrecognizable role in promoting papilloma formation, which disrupted epithelial stem cell homeostasis/maintenance. A follow-up study demonstrated that [ 28 ], in a K15-KRASG12D mouse model, IL-27 accelerated the accumulation of endothelin A receptor-positive CD11b cells, a novel category of protumor inflammatory cells, thus establishing a premalignant niche and expanding the mutation of stem cells. In patients with squamous cell carcinoma, the distribution of IL-27 receptor subunit alpha-positive cells in the stroma was shown to be closely correlated to tumor dedifferentiation.…”

Section: Discussionmentioning

confidence: 99%

Exploration of the Immune-Related Signatures and Immune Infiltration Analysis in Melanoma

Zhu

Gao

et al. 2021

Analytical Cellular Pathology

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In the present study, we aimed to investigate immune-related signatures and immune infiltration in melanoma. The transcriptome profiling and clinical data of melanoma were downloaded from The Cancer Genome Atlas database, and their matched normal samples were obtained from the Genotype-Tissue Expression database. After merging the genome expression data using Perl, the limma package was used for data normalization. We screened the differentially expressed genes (DEGs) and obtained immune signatures associated with melanoma by an immune-related signature list from the InnateDB database. Univariate Cox regression analysis was used to identify potential prognostic immune genes, and LASSO analysis was used to identify the hub genes. Next, based on the results of multivariate Cox regression analysis, we constructed a risk model for melanoma. We investigated the correlation between risk score and clinical characteristics and overall survival (OS) of patients. Based on the TIMER database, the association between selected immune signatures and immune cell distribution was evaluated. Next, the Wilcoxon rank-sum test was performed using CIBERSORT, which confirmed the differential distribution of immune-infiltrating cells between different risk groups. We obtained a list of 91 differentially expressed immune-related signatures. Functional enrichment analysis indicated that these immune-related DEGs participated in several areas of immune-related crosstalk, including cytokine-cytokine receptor interactions, JAK–STAT signaling pathway, chemokine signaling pathway, and Th17 cell differentiation pathway. A risk model was established based on multivariate Cox analysis results, and Kaplan-Meier analysis was performed. The Kruskal-Wallis test suggested that a high risk score indicated a poorer OS and correlated with higher American Joint Committee on Cancer-TNM (AJCC-TNM) stages and advanced pathological stages ( P < 0.01 ). Furthermore, the association between hub immune signatures and immune cell distribution was evaluated in specific tumor samples. The Wilcoxon rank-sum test was used to estimate immune infiltration density in the two groups, and results showed that the high-risk group exhibited a lower infiltration density, and the dominant immune cells included M0 macrophages ( P = 0.023 ) and activated mast cells ( P = 0.005 ).

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IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

Cited by 4 publications

References 53 publications

WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression

WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression

Inflammation: A key process in skin tumorigenesis (Review)

Exploration of the Immune-Related Signatures and Immune Infiltration Analysis in Melanoma

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