SKIL facilitates tumorigenesis and immune escape of NSCLC via upregulating TAZ/autophagy axis

AbstractImmune escape is an important mechanism in tumorigenesis. The aim of this study was to investigate roles of SKIL in tumorigenesis and immune escape of non-small-cell lung cancer (NSCLC). SKIL expression levels in NSCLC cell line, clinical sample, and adjacent normal tissue were measured by quantitative PCR, western blot, or immunohistochemistry. Lentivirus was used to overexpress/silence SKIL or TAZ expression. Malignant phenotypes of NSCLC cells were evaluated by colony formation, transwell, and MTT assays, and in xenograft mice model. Syngeneic mice model and flow cytometry were used to evaluate T cell infiltration. Quantitative PCR and western blot were applied to evaluate relevant mRNA and protein levels, respectively. Co-immunoprecipitation was applied to unveil the interaction between SKIL and TAZ. SKIL expression was higher in NSCLC tissue compared to adjacent normal tissue. Silencing of SKIL inhibited malignant phenotypes of NSCLC cells and promoted T cell infiltration. SKIL-knockdown inhibited autophagy and activated the STING pathway in NSCLC cells through down-regulation of TAZ. Silencing of TAZ cancelled the effects of SKIL overexpression on malignant phenotypes and autophagy of NSCLC cells. Inhibition of autophagy reversed the effects of SKIL/TAZ overexpression on the STING pathway. In conclusion, SKIL promoted tumorigenesis and immune escape of NSCLC cells through upregulation of TAZ/autophagy axis and inhibition on downstream STING pathway.

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Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽

10.3390/cancers12010057 ◽

2019 ◽

Vol 12 (1) ◽

pp. 57

Author(s):

Man-Chin Chen ◽

Christian Ronquillo Pangilinan ◽

Che-Hsin Lee

Keyword(s):

T Cell ◽

Tumor Growth ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Escape ◽

Cell Infiltration ◽

Tumor Immune Escape ◽

Programmed Death Ligand 1 ◽

T Cell Infiltration ◽

Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

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B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

Cell Death Discovery ◽

10.1038/s41420-021-00628-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jiayu Wang ◽

Hongya Wu ◽

Yanjun Chen ◽

Jinghan Zhu ◽

Linqing Sun ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Cell ◽

Immune Checkpoint ◽

Immune Escape ◽

Inverse Correlation ◽

Immune Checkpoint Blockade ◽

Cell Infiltration ◽

Tumor Immune Escape ◽

T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

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Patterns of CD8+ T-cell infiltration and immune escape mechanisms in head and neck cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.6078 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 6078-6078 ◽

Cited By ~ 2

Author(s):

Vassiliki Saloura ◽

Zhixiang Zuo ◽

Arun Khattri ◽

Holbrook Edwin Kohrt ◽

Mark W. Lingen ◽

...

Keyword(s):

Head And Neck Cancer ◽

T Cell ◽

Head And Neck ◽

Neck Cancer ◽

Immune Escape ◽

Cd8 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration ◽

Immune Escape Mechanisms

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PAX5 haploinsufficiency induces low T cell infiltration in the cancer microenvironment via reduced chemokines

Current Molecular Medicine ◽

10.2174/1566524021666211206094046 ◽

2021 ◽

Vol 21 ◽

Author(s):

Lei Wang ◽

Xue Liang ◽

Mi Liang ◽

Dang Li ◽

Jia Gu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Gene Editing ◽

Immune Escape ◽

Cell Infiltration ◽

Loss Of Function ◽

Wild Type ◽

T Cell Infiltration ◽

Wild Type Control

Aims: To investigate the effects of PAXT mutations on tumor immunity. Background: Loss of function of PAX5 plays a key role in PAX5 mutation tumor. Objective: PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape, but there was no report about mechanisms of PAX5 mutation inducing tumor immunological escape. Method: We constructed the PAX5 haplodeletion A20 cell lines using gene-editing technology, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on T cells and chemokines in the tumor microenvironment (TME). Result: Our results from different methods indicated percentages of CD3+ CD4+ T cells and CD3+ CD8+ T cells in TME of PAX5 haplodeletion clones decreased significantly compared with that of PAX5 wild type control. Several chemokines, such as Ccl2, Ccl4, Cxcl9 and Cxcl10, in TME of PAX5. Conclusion: Our study showed that PAX5 haploinsufficiency induced low T cell infiltration in TME using decreased chemokines.

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The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response

Cancers ◽

10.3390/cancers12030742 ◽

2020 ◽

Vol 12 (3) ◽

pp. 742 ◽

Cited By ~ 2

Author(s):

Rita Cabrita ◽

Shamik Mitra ◽

Adriana Sanna ◽

Henrik Ekedahl ◽

Kristina Lövgren ◽

...

Keyword(s):

T Cell ◽

Metastatic Melanoma ◽

Immune Evasion ◽

Immune Escape ◽

Therapy Response ◽

Predictive Biomarkers ◽

Cell Infiltration ◽

Pten Gene ◽

T Cell Infiltration

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.

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Identification of Driver Genes Regulating the T-Cell–Infiltrating Levels in Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.560546 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yi Cai ◽

Ying Tian ◽

Jianchu Wang ◽

Wang Wei ◽

Qianli Tang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Copy Number ◽

Target Genes ◽

Immune Escape ◽

Normal Liver ◽

Cell Infiltration ◽

Driver Genes ◽

Systematic Analysis ◽

T Cell Infiltration

The driver genes regulating T-cell infiltration are important for understanding immune-escape mechanisms and developing more effective immunotherapy. However, researches in this field have rarely been reported in hepatocellular carcinoma (HCC). In the present study, we identified cancer driver genes triggered by copy number alterations such as CDKN2B, MYC, TSC1, TP53, and GSK3B. The T-cell infiltration levels were significantly decreased in both HCC and recurrent HCC tissues compared with the adjacent normal liver tissues. Remarkably, we identified that copy number losses of MAX and TP53 were candidate driver genes that significantly suppress T-cell infiltration in HCC. Accordingly, their downstream oncogenic pathway, cell cycle, was significantly activated in the low T-cell infiltration HCC. Moreover, the chemokine-related target genes by TP53, which played key roles in T-cell recruitment, were also downregulated in HCC with TP53/MAX deletions, suggesting that copy number losses in MAX and TP53 might result in T-cell depletion in HCC via downregulating chemokines. Clinically, the T-cell infiltration levels and chemokines activity could accurately predict the response of sorafenib, and the prognostic outcomes in HCC. In conclusion, the systematic analysis not only facilitates identification of driver genes and signaling pathways involved in T-cell infiltration and immune escape, but also gains more insights into the functional roles of T cells in HCC.

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