Prognostic Biomarkers and Therapeutic Targets Identification Among CXC Chemokines in the Colon Adenocarcinoma Microenvironment

Abstract Background: COAD is among the most prevalent malignancy, with a very high incidence rate. Crosstalk between cancer and interstitial cells significantly affects cancer development, modulated partly by chemokines production. When present in the tumor microenvironment, CXC chemokines have been shown to regulate tumor cell activity and influence immune cell transport, resulting in anti-tumor immune mechanisms and influencing the outcomes of the patient; nonetheless, the CXC chemokines expression levels in COAD, as well as their prognostic significance, have not yet been established.Methods: This study used UALCAN, GeneMANIA, STRING, TRRUST, cBioPortal, TIMER, and GEPIA,Results: The expression of CXC1/2/3/5/6/11/12/13/14/16/17 in COAD patients was shown to be significantly correlated with the pathological stage. A considerably improved prognosis was observed in patients with low transcriptional levels of CXCL9/10/11. Differentially expressed CXC chemokines exert roles that are predominantly correlated with the chemokine signaling pathway and interactions of cytokine–cytokine receptors. Our findings indicated that the transcriptional factors, including SP1, RELA, and NFKB1 are essential for the production of CXC chemokines. Furthermore, we discovered a substantial association between the CXC chemokines production and infiltration of 6 kinds of immune cells (CD8+ T cells, dendritic cells, B cells, CD4+ T cells, neutrophils, and macrophages,). Conclusions: These findings might be useful in identifying prognostic indicators and immunotherapeutic targets for colon cancer.

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Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer

Cancers ◽

10.3390/cancers12113238 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3238

Author(s):

Mercedes Herrera ◽

Artur Mezheyeuski ◽

Lisa Villabona ◽

Sara Corvigno ◽

Carina Strell ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Immune Cell ◽

Therapeutic Potential ◽

Immune Surveillance ◽

Prognostic Significance ◽

Experimental Studies ◽

Population Based ◽

Good Prognosis ◽

High Group

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

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Integrative Analysis of Minichromosome Maintenance Proteins and Their Prognostic Significance in Melanoma

Frontiers in Oncology ◽

10.3389/fonc.2021.715173 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Han ◽

Yi-Zhu Wu ◽

Xiao-Yu Zhao ◽

Zhen-Hua Gong ◽

Guo-Liang Shen

Keyword(s):

T Cells ◽

Cell Cycle Progression ◽

Immune Cell ◽

Normal Skin ◽

Expression Patterns ◽

Prognostic Significance ◽

Mrna Levels ◽

Minichromosome Maintenance ◽

Prognostic Accuracy ◽

Mtorc1 Signaling

BackgroundMinichromosome maintenance (MCM) is known for participating in cell cycle progression, as well as DNA replication. While the diverse expression patterns and prognostic values of MCMs in melanoma still remained unclear.MethodsIn the present study, the transcriptional and clinical profiles of MCMs were explored in patients with melanoma from multiple databases, including GEO, TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, and TIMER databases.ResultsWe found that the elevated expressions of MCM2–6 and MCM10 were significantly expressed in melanoma compared to normal skin. High mRNA levels of MCM4, MCM5, and MCM10 were closely related to worse prognosis in patients with melanoma. GSEA showed hallmark pathways were most involved in mTORC1 signaling, G2M checkpoint, E2F targets, and mitotic spindle. Furthermore, we found potential correlations between the MCM expression and the immune cell infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells.ConclusionUpregulated MCM gene expression in melanoma probably played a crucial part in the development and progression of melanoma. The upregulated MCM4/5/10 expressions could be used as potential prognostic markers to improve the poor outcome and prognostic accuracy in patients with melanoma. Our study might shed light on the selection of prognostic biomarkers as well as the underlying molecular pathogenesis of melanoma.

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DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

10.1101/587105 ◽

2019 ◽

Cited By ~ 3

Author(s):

Xiao Huang ◽

Jasper Z. Williams ◽

Ryan Chang ◽

Zhongbo Li ◽

Eric Gai ◽

...

Keyword(s):

T Cells ◽

Immune Cell ◽

Ex Vivo ◽

Cell Activity ◽

Engineered T Cells ◽

Advanced Biomaterials ◽

Cancer Immunotherapies ◽

Biodegradable Particles ◽

The Impact

Advanced biomaterials provide versatile ways to spatially and temporally control immune cell activity, potentially enhancing their therapeutic potency and safety. Precise cell modulation demands multi-modal display of functional proteins with controlled densities on biomaterials. Here, we develop an artificial immune cell engager (AICE) platform – biodegradable particles onto which multiple proteins are densely loaded with ratiometric control via short nucleic acid tethers. We demonstrate the impact of AICE with varying ratios of anti-CD3 and anti-CD28 antibodies onex vivoexpansion of human primary T cells. We also show that AICE can be used to control the activity of engineered T cellsin vivo. AICE injected intratumorally can provide a local priming signal for systemically administered AND-gate chimeric antigen receptor T cells, driving local tumor clearance while sparing uninjected tumors that model potentially cross-reactive healthy tissues. This modularly functionalized biomaterial thus provides a flexible platform to achieve sophisticated control over cell-based immunotherapies.

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ANTIBODY-INDEPENDENT ANTITUMOR EFFECTS OF CD32A-CHIMERIC RECEPTOR T CELLS: IMPLICATIONS FOR BREAST CANCER PROGNOSIS AND TREATMENT.

10.1101/2021.12.22.473841 ◽

2021 ◽

Author(s):

Giuseppe Sconocchia ◽

Giulia Lanzilli ◽

Valeriana Cesarini ◽

Domenico Alessandro Sivestris ◽

Roberto Arriga ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Cell Surface ◽

Prognostic Significance ◽

Cell Activity ◽

Cancer Prognosis ◽

Chimeric Receptor ◽

Antitumor Effects ◽

Down Regulation

FcγRIIA (CD32A) and their ligands, including the immunoglobulin Fc fragment and pentraxins, are key players in a variety of innate immune responses. Still unclear is whether additional ligands of CD32A do exist. The objective of this study is to demonstrate that CD32A-chimeric receptor (CR) can be utilized for the identification of CD32A cell surface ligand(s). Among fifteen cancer cell lines tested, CD32A-CR T cells recognized three of breast cancer (BC) including the MDA-MB-468 and one colorectal carcinoma (HT29) in the absence of targeting antibodies. Conjugation of sensitive BC cells with CD32A-CR T cells induced CD32A polarization and down-regulation, CD107 release, and mutual cell elimination in vitro. Conversely, normal fibroblasts and myoblasts were not affected while normal HUVEC cells promoted CD32A down-regulation. CD32A-CR T cell activity was not inhibited by human IgGs or human serum, but; it was rather enhanced by cetuximab antibody. RNAseq analysis of sensitive vs resistant BC cells identified a fingerprint of 42 genes predicting the sensitivity of BC cells to CD32A-CR T cells and their association with favorable prognostic significance in advanced BC patients. Our data also identify ICAM 1 as a major regulator of CD32A-CR T cell-mediated cytotoxicity. Finally, CD32A-CR T cell administration protected immunodeficient mice from subcutaneous growth of MDA-MB-468 cells in the absence of tumor-specific antibodies. These data indicate that CD32A-CR can be utilized for the identification of (1) cell surface CD32A ligand(s); (2) rational therapeutic strategies to target BC; and (3) novel transcriptomic signatures prognostically relevant for advanced BC patients.

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Mutations Status of Chemokine Signaling Pathway Predict Prognosis of Immune Checkpoint Inhibitors in Colon Adenocarcinoma

Frontiers in Pharmacology ◽

10.3389/fphar.2021.721181 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anqi Lin ◽

Wentao Xu ◽

Peng Luo ◽

Jian Zhang

Keyword(s):

Signaling Pathway ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Colon Adenocarcinoma ◽

Cox Regression Analysis ◽

Chemokine Signaling ◽

Number Of Patients ◽

Chemokine Signaling Pathway ◽

The Relationship

In recent years, tumor immunotherapy has become an important treatment program and popular research focus. However, the use of immune checkpoint inhibitors (ICI) in the treatment of colorectal cancer still has limitations due to the current markers only being able to predict the prognosis of a small number of patients. As the chemokine signaling pathway can promote the anti-tumor response of the immune system by recruiting immune cells, we explored the relationship between mutations in the chemokine signaling pathway and the prognosis of colon adenocarcinoma (COAD) patients receiving ICI treatment. To analyze the relationship between chemokine mutation status and the prognosis of patients receiving ICI treatment, clinical and mutation data, with immunotherapy, for a COAD cohort was obtained from “cbioportal.” Then, combining this with COAD cohort data from The Cancer Genome Atlas (TCGA) database, the panorama of gene mutation, immunogenicity, and difference in tumor microenvironment (TME) of chemokine pathways with different mutation statuses were analyzed. High-mut status has been proved to be a prognostic indicator of COAD patients receiving ICI treatment by Univariate and Multivariate Cox regression analysis. CIBERSORT analysis showed that the infiltration degree of M1 macrophages, neutrophils, and activated natural killer (NK) cells was higher in those with high-mut status. Immunogenicity of the high-mut group was also significantly increased, with the mutation number of tumor mutation burden (TMB), neoantigen load (NAL), DNA damage repair (DDR) pathway and microsatellite instability biomarker (MSI-H) being significantly higher. In this study, we found that the mutation state of chemokine pathways is closely associated with the prognosis of COAD patients undergoing ICI treatment. The higher number of TMB, NAL, and DDR mutations and inflammatory TME, may be the mechanism of behind a better prognosis. This discovery provides a possible idea for ICI therapy of COAD.

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6,7,4′-Trihydroxyflavanone Prevents Methamphetamine-Induced T Cell Deactivation by Protecting the Activated T Cells from Apoptosis

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500051 ◽

2021 ◽

pp. 1-17

Author(s):

Hyun-Su Lee ◽

Gil-Saeng Jeong

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Immune Cell ◽

Therapeutic Potential ◽

Cell Activity ◽

Activated T Cells ◽

Study Results ◽

Apoptotic Proteins ◽

Pre Treatment

Methamphetamine (METH) is an extremely addictive drug that has raised serious public health concerns recently. METH addiction not only results in neuronal cytotoxicity, but it also affects immune cell activity, including T lymphocytes. 6,4,7[Formula: see text]-trihydroxyflavanone (THF), isolated from Dalbergia odorifera, has been studied for its antibacterial activity, but evidence for whether THF has an anti-cytotoxic and protective effect on T cell activation exposed to METH is lacking. In this study, results showed that treatment with THF was not cytotoxic to Jurkat T cells but dose-dependently mitigated the cytotoxicity induced by exposure to METH. The Western blot results demonstrating pre-treatment with THF maintained the expression of anti-apoptotic proteins and phosphorylation of PI3K/Akt/mTOR downregulated by treatment with METH. Furthermore, we found that decreased expression of IL-2 and CD69 by METH exposure was partially restored, and viability was significantly prevented by pre-treatment with THF in activated T cells. These findings were involved in re-elevated expression of anti-apoptotic proteins as well as recovered pathways including MAPK/PI3K/Akt/mTOR in activated T cells pre-exposed to METH. Our results suggest beneficial effects of THF against the cytotoxic and immune-modulating effect of METH on T cells and therapeutic potential of THF for patients with immunodeficiency caused by METH addiction.

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LTBP2 Serves as a Prognostic Biomarker and Correlated with the Immune Infiltration in Stomach and Colon Cancer

10.21203/rs.3.rs-462150/v1 ◽

2021 ◽

Author(s):

Shuai Chen ◽

Zhihuai Wang ◽

Yu Gong ◽

Hanyang Liu ◽

Haojun Yang ◽

...

Keyword(s):

T Cells ◽

Immune Cells ◽

Transforming Growth Factor ◽

Immune Cell ◽

Disease Free Survival ◽

Colon Adenocarcinoma ◽

Progression Free Survival ◽

Transforming Growth Factor Β ◽

Gene Markers ◽

Free Survival

Abstract Latent transforming growth factor β binding protein 2 (LTBP2) involved in the TGF pathway to induce immunosuppression and immune response. However, the association between the outcome of patients, the infiltrating immune cell and LTBP2 expression is still unclear in human cancers. The LTBP2 expression was analyzed by TIIMER and Oncomine database. Based on the Prognoscan database, the GEPIA database, and the Kaplan-Meier plotter database, the prognostic value was assessed. The immune and stromal score of tumors was calculated through ESTIMATE. We additionally explore the relationship among the LTBP2 expression, the infiltrating immune cells, and its gene markers in the TIMER, TISIDB, and GEPIA database, the enriched KEGG pathways of LTBP2 were evaluated by GSEA. The result showed that LTBP2 expressed differently among the normal and tumor tissues in various sorts of cancer involving stomach adenocarcinoma (STAD) and colon adenocarcinoma (COAD), and three cohorts of COAD presented that the LTBP2 high expression was linked with poorer disease-free survival and the elevated LTBP2 expression correlated with progression-free survival and poorer overall survival in STAD. The LTBP2 was correlated with the stromal and immune score in different cancers. The infiltrating immune cells include the CD8+T cells and CD4+T cells, macrophages, neutrophils, and dendritic cells were correlated with the LTBP2 expression. Meanwhile, LTBP2 was related to the infiltrating immune cell’s gene markers and enriched immune-related pathways in STAD and COAD. LTBP2 was the potential to be an independent predictor for the prognosis and a new target for immunotherapy in STAD and COAD.

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Regulatory T Cells Improved the Anti-cirrhosis Activity of Human Amniotic Mesenchymal Stem Cell in the Liver by Regulating the TGF-β-Indoleamine 2,3-Dioxygenase Signaling

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.737825 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zhenhua Deng ◽

Jinren Zhou ◽

Xiaoxin Mu ◽

Jian Gu ◽

Xiangyu Li ◽

...

Keyword(s):

T Cells ◽

Liver Fibrosis ◽

Regulatory T Cells ◽

Mesenchymal Stromal Cell ◽

Immune Cell ◽

Cell Activity ◽

Indoleamine 2,3 Dioxygenase ◽

Current Therapies ◽

Hepatocyte Growth

Liver fibrosis is a progression stage of chronic liver disease, while current therapies cannot cure or attune cirrhosis effectively. Human amniotic mesenchymal stromal cell (hAMSC) presented immunoregulatory and tissue repairability of multiple illnesses. Regulatory T cells (Treg) had been proved to be functional in reducing immune cell activity. We showed that co-infusion of hAMSC and Treg prevented mild liver fibrosis comparing with hAMSC or Treg alone group. In vitro study indicated that the addition of Treg or the supernatant of Treg improved the hepatocyte growth factor (HGF) secreting and cell differentiation ability of hAMSC. Reduction of TGF-β significantly decreased the HGF secreting and differentiation of hAMSC. Multiple signal neutralizers were added to the culture to understand further the mechanism, which showed that 1-MT, the suppressor of Indoleamine 2,3-dioxygenase (IDO), was involved in the effect of TGF-β in regulating hAMSC. Depletion of TGF-β or IDO signaling successfully abolished the effect of Treg in improving hAMSC’s function both in vitro and vivo. Finally, our result indicated that Treg improved the function of hAMSC by regulating the TGF-β-IDO signaling and co-infusion of hAMSC and Treg provided a promising approach for treating liver cirrhosis.

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The study of the significance and prognosis of the differential expressed miRNAs and their target genes associated with biological in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15088 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15088-e15088

Author(s):

Mingyun Wang ◽

Mi Yang

Keyword(s):

Colorectal Cancer ◽

Target Genes ◽

Biological Significance ◽

Differentially Expressed ◽

Prognostic Indicators ◽

Receptor Interaction ◽

Ppi Network ◽

Prognostic Information ◽

Chemokine Signaling ◽

Chemokine Signaling Pathway

e15088 Background: MicroRNAs (miRNAs) have been related to prognostic indicators (such as stage and survival) in colorectal cancer. This study aimed to identify differentially expressed miRNAs and their target genes associated with biological significance and prognosis in colorectal cancer. Methods: The colorectal cancer, colorectal adenoma, and normal samples were obtained from the gene expression profile of GSE71187. A union of differentially expressed genes (DEGs) in the three groups was identified. The significantly different modules with highly interconnected DEGs were identified using weighted correlation network analysis (WGCNA) and were enriched to the KEGG pathway and GO function. Subsequently, the protein-protein interaction (PPI) network for DEGs in the module and the integrated regulatory network of miRNA-DEGs were constructed. In addition, the relationship of target DEGs and prognostic information was analyzed. Results: Three significantly different modules were identified, such as the brown, turquoise, and grey modules. The turquoise module including LTC4S, KLRK1, UNC5C, etc., which was mainly enriched to cell adhesion, cytokine−cytokine receptor interaction, and chemokine signaling pathway, inhibited the development of colorectal cancer. Subsequently, PPI network was constructed with the 678 DEGs in the three modules. Moreover, the miRNA-DEGs network was constructed with the 17 target DEGs (CXCR1, LTC4S, BTK, IGF1, etc.) and 14 miRNA (hsa-miR-335-5p, etc.). Finally, the overexpressed LTC4S was a good prognostic biomarker for colorectal cancer. Conclusions: The hsa-miR-335-5p might have potential prognosis value by targeting LTC4S and CXCR1 in colorectal cancer.

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Correlation between tumor infiltrating immune cells and peripheral regulatory T cell determined using methylation analyses and its prognostic significance in resected gastric cancer

PLoS ONE ◽

10.1371/journal.pone.0252480 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252480

Author(s):

Koung Jin Suh ◽

Jin Won Kim ◽

Ji Eun Kim ◽

Ji Hea Sung ◽

Jiwon Koh ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

T Cell ◽

Cell Density ◽

Immune Cell ◽

Prognostic Significance ◽

Disease Free Survival ◽

Prognostic Information ◽

Curative Surgery ◽

Cd4 Cell

Peripheral regulatory T cells (pTregs) are a highly immunosuppressive fraction of CD4+ T cells. We aimed to evaluate the clinical significance of pTregs in patients with gastric cancer and to determine the correlation between pTregs and immune cell infiltration in tumor microenvironment. pTregs status was determined by assessing the pTreg/total T-cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation, so-called Cellular Ratio of Immune Tolerance “ImmunoCRIT”) using methylation analyses in 433 patients with gastric cancer who received curative surgery. Among 422 evaluable patients, 230 (54.5%) had high ImmunoCRIT (> 21.0). Patients with high ImmunoCRIT had significantly shorter disease-free survival (DFS) and overall survival (OS) than those with high ImmunoCRIT (p = 0.030, p = 0.008, respectively). In multivariate analysis, high ImmunoCRIT kept a prognostic role for shorter OS (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4–2.9; p = 0.005). CD3+ cell density and CD4+ cell density was significantly higher within the tumor in high ImmunoCRIT group than those in low ImmunoCRIT group (CD3+ cell, 202.12/mm2 vs. 172.2/mm2, p = 0.029; CD4+ cell, 56.5/mm2 vs. 43.5/mm2, p = 0.007). In conclusion, the peripheral ImmunoCRIT determined by epigenetic methylation analysis provides prognostic information in resected gastric tumors.

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