scholarly journals ERBB1/2/3 Expression, Prognosis, and Immune Infiltration in Cutaneous Melanoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shougang Liu ◽  
Rong Geng ◽  
Eryi Lin ◽  
Peizhen Zhao ◽  
Yongfeng Chen
Keyword(s):  
T Cells ◽  
Cutaneous Melanoma ◽  
Normal Skin ◽  
Disease Free Survival ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Erbb Family ◽  
Immune Infiltration ◽  
Melanoma Patients ◽  
The Relationship

BackgroundThe four ERBB tyrosine kinase family members [ERBB1 (epidermal growth factor receptor, EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4)] (ERBB receptor family) have been shown, according to previous studies, to be related to the cutaneous melanoma. ERBB3 is the only member of the ERBBs that lacks tyrosine kinase activity and thus needs to dimer with other tyrosine kinases receptors to trigger the signaling pathway, while ERBB3 may dimer with all members of the ERBB family. Melanoma progression depends on activation of ERBB signaling, especially the ERBB3/ERBB2 cascade. There are lymphocytes and T cell infiltrates in melanoma. Numerous pieces of evidences indicate that local immune status plays an important role in the formation of anti-tumor immune responses. However, the relationship between the ERBBs and prognosis and immune infiltration in cutaneous melanoma is not completely clear.MethodsThe expression of the ERBBs was analyzed through the Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA), respectively. Immunohistochemistry of ERBBs was obtained from the Human Protein Atlas is increased before HPA database. ERBBs genes expression and mutation analysis in cutaneous melanoma from the cBioPortal. Functional annotation and Kyoto Encyclopedia of Genes and Genomes is increased before KEGG pathway enrichment analysis from the Metascape. Correlations between ERBBs and 31 genes that were close to each other and frequently altered were explored by GEPIA. Using the GEPIA database, we also investigated the relationship between ERBBs and myeloid-derived suppressor cells (MDSC) in cutaneous melanoma. The disease-free survival and different tumor stages of ERBBs were evaluated by GEPIA. The correlation of ERBBs and tumor-infiltrating immune cells and prognostic(5 years survival rates) was tested by the Tumor Immune Estimation Resource (TIMER).ResultsIn general, the expression levels of ERBB1/2 in cutaneous melanoma were lower than those in normal skin tissue. By contrast, the ERBB3 expression level was higher in cutaneous melanoma than in normal skin tissue. Low expression of ERBB1/2 and high expression of ERBB3 were detrimental to the 5 years survival of cutaneous melanoma patients (ERBB1: log-rank P: 0.03; ERBB2: log-rank P: 0.008; ERBB3: log-rank P: 0.039). ERBB4 expression may not affect the prognosis of patients with cutaneous melanoma. ERBBs may not play a role in the tumor stage and disease-free survival in cutaneous melanoma patients. The relationship between the ERBB family and 31 genes that were close to each other and frequently altered is demonstrated as the genes regulated by the ERBB family being mainly concentrated in the RAS/RAF/MEK/ERK signaling pathway. ERBB2 can induce infiltration of CD8+ T cells and B cells, while ERBB3 can induce infiltration of CD4+ T cells, CD8+ T cells, and Neutrophil cells. ERBBs are more significantly associated with M1 macrophages, dendritic cells, Th1, Th2, Th17, and Treg cellular immune markers (Cor > 0.2). ERBB2/3 were related to MDSC in cutaneous melanoma, including human mononuclear myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), and may influence the progression of cutaneous melanoma through MDSC, but the conclusion needs further probing.ConclusionThis study investigated the prognosis and immune infiltration of the ERBB family in cutaneous melanoma. Our results suggest that ERBB1/2/3 may serve as early prognostic markers and potential therapeutic targets in cutaneous melanoma.

Preclinical and clinical studies of a class I/IV HDAC inhibitor, mocetinostat, in melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10052-10052
Author(s):  
Jeffrey S. Weber ◽  
Andressa S Laino ◽  
Melinda Vassallo ◽  
Anna Pavlick ◽  
Saundra Malatyali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Metastatic Melanoma ◽  
Hdac Inhibitor ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Hdac Inhibition ◽  
Melanoma Patients ◽  
Grade 3

10052 Background: Mocetinostat is a class I/IV HDAC inhibitor with HDAC1/2/3/11 activity. Preclinical murine data suggest that HDAC inhibition has immune activity and may augment the clinical benefit of checkpoint inhibition. Several trials are assessing the effects of adding HDAC inhibition to PD-1 blockade. Methods: Patients with therapy-naive metastatic melanoma were treated in a pilot phase Ib trial with nivolumab at 3 mg/kg/ipilimumab at 1 mg/kg every three weeks four times and a starting dose of mocetinostat at 70 mg orally three times a week in a 12-week induction cycle followed by 12-week maintenance cycles of nivolumab 240 mg every 2 weeks and mocetinostat at the same dose and schedule as induction. Endpoints were toxicity, definition of a recommended phase 2 dose and preliminary assessment of response as well as correlative marker determination. Peripheral blood mononuclear blood cells from patients were tested in vitro at varying concentrations of mocetinostat, and its impact on T, regulatory T and myeloid-derived suppressor cell phenotypes were assessed by flow cytometry, as well as cytokine production by Luminex. Results: In the mocetinostat, nivolumab and ipilimumab phase I trial, 10 patients were treated, including 5 males and 5 females with a median age of 59. There were 2 complete and 5 partial responses confirmed; 6 of 7 are maintained at a median of 16 months of follow up. Three patients had progressive disease. Seven patients had grade 3-4 immune related adverse events; in 3 they were multiple. No patients died. In vitro, mocetinostat at doses from 125 to 500 nM increased relative percentage of CD4/CD8 central memory T cells, and decreased IL-6 levels while increasing interferon-gamma production (p = 0.005). Percentages of regulatory T and monocytic myeloid-derived suppressor cells were decreased by mocetinostat (p = 0.005), which also down-modulated regulatory T cell function by reducing FOXP3, HELIOS and GARP (p = 0.001). Conclusions: In vitro, mocetinostat promoted accumulation of central memory CD8 and CD4 T cells from melanoma patients, and decreased percentages and suppressive activity of T regulatory cells and myeloid-derived suppressor cells. In a pilot clinical trial, mocetinostat combined with nivolumab and ipilimumab in treatment-naïve metastatic melanoma patients exhibited a response rate of 70% with long duration of response but all ten patients treated had at least one grade 3 or 4 immune-related toxicity. De-escalation of the mocetinostat dose to 50 mg three times a week was felt to be indicated due to the toxicity of the triple regimen. Clinical trial information: NCT03565406.

scholarly journals Sirt1 Expression Related with Sarcoma Growth after Stem Cell Transplantation Combined with Depletion of Myeloid-Derived Suppressor Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5796-5796
Author(s):  
Ming Li ◽  
Ming Shi ◽  
Yunze Cui ◽  
Yasushi Adachi ◽  
Susumu Ikehara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Malignant Tumors ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Sirt1 Expression ◽  
Cell Transplants ◽  
The Relationship

Abstract Sirtuins (Sirt) play a number of roles in various aging-related diseases such as obesity, diabetes and cancer, and Sirt1 plays a double role in cancer. The combination of bone marrow transplantation (BMT) and thymus transplantation (TT) has been shown to prevent the growth of malignant tumors. Myeloid-derived suppressor cells (MDSCs) can differentiate from bone marrow stem cells under pathological conditions such as cancer, and prevent the potent action of T cells and NK cells, thereby promoting tumor growth. Thus, depleting MDSCs is important when treating cancer. We therefore investigated the relationship between Sirt1 expression and sarcoma growth in sarcoma-bearing mice treated with BMT+TT and the depletion of MDSCs using Gr-1 Ab. Our results showed that only granulocytic MDSCs (G-MDSCs) were depleted by the Gr-1 Ab in these mice. Moreover, the sarcomas decreased significantly in size in the Gr-1 antibody group when compared with the BMT group. This was due to the increase in the percentage of T cells and decrease in the percentage of G-MDSCs. Furthermore, Sirt1 expression decreased significantly in the sarcoma. These findings suggest that inactive Sirt1 may prevent sarcoma growth in sarcoma-bearing mice that receive stem cell transplants and depletion of MDSCs. Disclosures No relevant conflicts of interest to declare.

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

scholarly journals Reciprocal Relationship between Myeloid-Derived Suppressor Cells and T Cells

2013 ◽  
Vol 191 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Srinivas Nagaraj ◽  
Je-In Youn ◽  
Dmitry I. Gabrilovich
Keyword(s):  
T Cells ◽  
Suppressor Cells ◽  
Reciprocal Relationship ◽  
Myeloid Derived Suppressor Cells

scholarly journals Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Lamsfus Calle ◽  
Rolf Fendel ◽  
Anurag Singh ◽  
Thomas L. Richie ◽  
Stephen L. Hoffman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Controlled Human Malaria Infection

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

scholarly journals CDCA3 Is a Novel Prognostic Biomarker Associated with Immune Infiltration in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Zhihuai Wang ◽  
Shuai Chen ◽  
Gaochao Wang ◽  
Sun Li ◽  
Xihu Qin
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Cell ◽  
Disease Free Survival ◽  
In Silico Analysis ◽  
Gene Markers ◽  
Free Survival ◽  
Immune Infiltration ◽  
Normal Tissues ◽  
Tumor Tissues

Cell division cycle-associated protein-3 (CDCA3) contributes to the regulation of the cell cycle. CDCA3 plays an important role in the carcinogenesis of various cancers; however, the association between CDCA3 expression, prognosis of patients, and immune infiltration in the tumor microenvironment is still unknown. Here, we demonstrated that CDCA3 was differentially expressed between the tumor tissues and corresponding normal tissues using in silico analysis in the ONCOMINE and Tumor Immune Estimation Resource (TIMER) databases. We analyzed the relationship between the expression of CDCA3 and prognosis of patients with hepatocellular carcinoma (HCC) using the Kaplan–Meier plotter database and Gene Expression Profiling Interactive Analysis (GEPIA). Furthermore, we determined the prognostic value of CDCA3 expression using univariate and multivariate analyses. We observed that CDCA3 expression closely correlated with immune infiltration and gene markers of infiltrating immune cells in the TIMER database. CDCA3 was highly expressed in the tumor tissues than in the adjacent normal tissues in various cancers, including HCC. Increased expression of CDCA3 was accompanied by poorer overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). The correlation between CDCA3 expression and OS and disease-free survival (DFS) was also studied using GEPIA. CDCA3 expression was associated with the levels of immune cell infiltration and was positively correlated with tumor purity. Moreover, CDCA3 expression was associated with gene markers such as PD-1, CTLA4, LAG3, and TIM-3 from exhausted T cells, CD3D, CD3E, and CD2 from T cells, and TGFB1 and CCR8 located on the surface of Tregs. Thus, we demonstrated that CDCA3 may be a potential target and biomarker for the management and diagnosis of HCC.

scholarly journals An Inflammatory Profile Correlates With Decreased Frequency of Cytotoxic Cells in Coronavirus Disease 2019

2020 ◽  
Vol 71 (16) ◽  
pp. 2272-2275 ◽  
Author(s):  
Veronica Bordoni ◽  
Alessandra Sacchi ◽  
Eleonora Cimini ◽  
Stefania Notari ◽  
Germana Grassi ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
T Cells ◽  
Intensive Care ◽  
Inflammatory Cytokines ◽  
Suppressor Cells ◽  
Lower Number ◽  
Myeloid Derived Suppressor Cells ◽  
Icu Patients ◽  
Cytotoxic Cells ◽  
Inflammatory Profile

Abstract Increased production of inflammatory cytokines and myeloid-derived suppressor cells occurs in patients with coronavirus disease 2019. These inversely correlated with perforin-expressing natural killer (NK) and CD3+ T cells. We observed a lower number of perforin-expressing NK cells in intensive care unit (ICU) patients compared with non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.

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