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

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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Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-11-2479 ◽

2011 ◽

Vol 18 (5) ◽

pp. 1386-1394 ◽

Cited By ~ 423

Author(s):

James S. Wilmott ◽

Georgina V. Long ◽

Julie R. Howle ◽

Lauren E. Haydu ◽

Raghwa N. Sharma ◽

...

Keyword(s):

T Cell ◽

Metastatic Melanoma ◽

Cell Infiltration ◽

Braf Inhibitors ◽

T Cell Infiltration

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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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Predominant donor CD103+CD8+ T cell infiltration into the gut epithelium during acute GvHD: a role of gut lymph nodes

International Immunology ◽

10.1093/intimm/dxm153 ◽

2008 ◽

Vol 20 (3) ◽

pp. 385-394 ◽

Cited By ~ 23

Author(s):

Shu Zhou ◽

Hisashi Ueta ◽

Xue-Dong Xu ◽

Changde Shi ◽

Kenjiro Matsuno

Keyword(s):

T Cell ◽

Lymph Nodes ◽

Acute Gvhd ◽

Cd8 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration ◽

Gut Epithelium

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Translating transcriptome to immunophenotype in head and neck squamous cell carcinoma (HNSCC) to identify pathways promoting T-cell infiltration.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17542 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17542-e17542

Author(s):

Theodoros Rampias ◽

Christos K. Kontos ◽

Alexandros Polyzos ◽

Aris Giotakis ◽

Evangelos Giotakis ◽

...

Keyword(s):

T Cell ◽

Checkpoint Inhibitors ◽

Predictive Biomarkers ◽

Keratinocyte Differentiation ◽

Cell Infiltration ◽

Mrna Levels ◽

Rna Seq ◽

Mesenchymal Transition ◽

Invasive Margin ◽

T Cell Infiltration

e17542 Background: We sought to analyze the transcriptional landscape of HNSCC in an attempt to identify tumor-intrinsic oncogenic pathways that appear to mediate T-cell infiltration of tumor tissue. In this direction, we employ a methodology that integrates histopathology data of the tumor microenvironment with its corresponding transcriptome. Methods: 32 frozen HNSCCs were subjected to RNA-seq and corresponding FFPE were scored for plasma cells, tertiary lymphoid structures and CD8a+ TILs (center, invasive margin). RNA-seq data were analyzed to identify differentially expressed genes (DEGs) between tumors scored by immunohistochemistry (IHC) as CD8a high and CD8a low. Gene ontology analysis (GO) was performed based on DEGs > 1.5 fold expression change between CD8a high and CD8a low groups. Candidate genes were investigated by hierarchical clustering in TCGA RNA-seq data and further validated by IHC and quantitative RT-PCR in our cohort. Results: 32 HNSCCs were either scored as CD8a high or CD8a low based on IHC detection of CD8a+ cells in invasive margin of tumors. Comparative analysis of mRNA expression data between CD8a high and CD8a low groups in our cohort revealed that Muc1/16 overexpression and glycosylation was highly enriched in T cell infiltrated group of tumors. This finding was further validated using antibodies that detect glycosylated epitopes for both mucins. Analysis of TCGA RNA-seq data indicated that Muc1/16 overexpressing tumors share signatures of early keratinocyte differentiation and stem cell identity and co-express high levels of enzymes that promote Muc1/16 glycosylation. Interestingly, loss of CDH1 and acquisition of epithelial mesenchymal transition (EMT) markers in the cluster of Muc1/16 overexpressing tumors is strongly correlated with elevated CD8a, IDO1, CD274 and CXCL10 mRNA levels (P < 0.0001). Conclusions: Muc1/16 overexpressing tumors represent a very immunogenic HNSCC cluster. Previous studies have shown that mucins 1 and 16 in cancer cells expose glycosylated-specific epitopes that are recognized by T cells as cancer antigens. To this end, MUC1/16 expression may serve as predictive biomarkers for response to immunotherapy and MUC-targeted immunotherapy may function as an attractive partner to checkpoint inhibitors in HNSCC.

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Renal oxidative stress and renal CD8+ T-cell infiltration in mercuric chloride-induced nephropathy in rats: role of angiotensin II

Journal of Immunotoxicology ◽

10.3109/1547691x.2015.1089960 ◽

2015 ◽

Vol 13 (3) ◽

pp. 324-334 ◽

Cited By ~ 1

Author(s):

Caterina Peña ◽

Juan P. Hernández-Fonseca ◽

Adriana Pedreañez ◽

Ninoska Viera ◽

Jesús Mosquera

Keyword(s):

Oxidative Stress ◽

T Cell ◽

Angiotensin Ii ◽

Mercuric Chloride ◽

Cd8 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration

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Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2008.05746.x ◽

2008 ◽

Vol 107 (6) ◽

pp. 1741-1752 ◽

Cited By ~ 47

Author(s):

D. Gómez-Nicola ◽

B. Valle-Argos ◽

M. Suardíaz ◽

J. S. Taylor ◽

M. Nieto-Sampedro

Keyword(s):

Spinal Cord ◽

T Cell ◽

Sciatic Nerve ◽

Chronic Constriction Injury ◽

Cell Infiltration ◽

T Cell Infiltration

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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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OTME-20. Chitinase-3-like-1(CHI3L1) Protein Complexes Regulate the immunosuppressive Microenvironment in Glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.071 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii17-ii18

Author(s):

Apeng Chen ◽

Yinan Jiang ◽

Zhengwei Li ◽

Xiangwei Xiao ◽

Dean Yimlamai ◽

...

Keyword(s):

T Cell ◽

Immune Evasion ◽

Protein Complexes ◽

Immune Surveillance ◽

Cell Infiltration ◽

Binding Motif ◽

T Cell Infiltration ◽

Pathway Activation ◽

Galectin 3 ◽

Immunosuppressive Microenvironment

Abstract Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

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

Cell Death and Disease ◽

10.1038/s41419-020-03200-7 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Fang Ma ◽

Meng-Ge Ding ◽

Yi-Yu Lei ◽

Li-Hua Luo ◽

Shun Jiang ◽

...

Keyword(s):

T Cell ◽

Western Blot ◽

Quantitative Pcr ◽

Normal Tissue ◽

Immune Escape ◽

Cell Infiltration ◽

Adjacent Normal Tissue ◽

Mice Model ◽

T Cell Infiltration ◽

Sting Pathway

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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