Tumor-Specific Nascent Nine-Peptide-Epitopes Prediction and Bioinformatics Characterization in Human Colorectal Cancer

2020 ◽  
Vol 10 (6) ◽  
pp. 1338-1345
Author(s):  
Ying Zhu ◽  
Bo Hu ◽  
Long Xu ◽  
Lili Yang ◽  
Congjie Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Translesion Synthesis ◽  
Gene Mutations ◽  
Wild Type ◽  
Peptide Epitopes ◽  
Binding Force ◽  
Tumor Tissues ◽  
Mutant Genes

Background/Aims: Neoantigens are peptides produced by translation of mutant exons and existed in tumor tissues instead of normal tissues, thus, we desired to investigate the antigenic peptide epitopes of cancerspecific neoantigen, to detect the affinity of the nonapeptide with the corresponding Human Leukocyte Antigen I (HLA I) allele molecule, in order to understand the relationship of mutant exon genes of Colorectal Cancer (CRC) patients and the drive genes that are currently known for tumorigenesis of CRC. Methods: The next generation sequencing (NGS) method was used to detect the whole genome sequence and HLA I allele types of tumor tissues and adjacent tissues of 5 CRC patients. pVAC-Seq was applied to identify the nascent nonapeptides generated from exon mutations. The affinity of polypeptides with respective HLA I molecules in CRC was calculated by using NETMHC 4.0 Server. The molecular localization, molecular function, and signal pathways of mutant genes in 5 CRC patients were performed by FunRich 3.1.3 software. The TIMER website was applied to predict the analysis of intratumoral immune cell infiltration associated with the gene mutations in 5 CRC patients. Results: Fifty-six tumor-specific neo-nonapeptides were predicted from 54 different exon gene mutations. The 56 tumor new nonapeptide sequences were different from the shared motif of the HLA I allele. We explored that the tumor-specific nascent nonapeptide mainly bound to HLA-A.02*03, HLA-B.58*01 and HLA-B.11*01, and the affinity analysis results suggested that 14 of the nonapeptides had strong binding force, 20 nonapeptides had weak binding force, and 22 nonapeptides had no binding force. 54 mutant exons of 5 CRC patients were chiefly located in Leading edge membrane, Fanconi anaemia nuclear complex, and Azurophil granule. The molecular functions of these genes were involved in DNA-directed DNA polymerase activity, Vitamin or cofactor transporter activity, and Receptor signaling protein tyrosine kinase activity. 54 gene mutations had key roles in Translesion synthesis by Pol zeta, Translesion synthesis by DNA polymerases bypassing lesion on DNA template, and DNA Damage Bypass. We found that the mutant FMN2 had more infiltration of CD8+ T cells in the tumor than the wild type, and the mutant ZNF717 had more infiltration of CD8+ T cells and neutrophils in the tumor than the wild type, the difference was statistically significant. Conclusion: This study provides a preliminary result to illustrate that the prediction and bioinformatics feature of tumor-specific new nine-peptide-epitopes in CRC. It is hoped that the cancer-specific neoantigen will be used for adjuvant immunotherapy after radical surgery of colorectal cancer, and the mutant genes of CRC can also be used as landmarks for postoperative recurrence and metastasis of colorectal cancer.

scholarly journals In vitro Evaluation of CMV Specific CD8+T Cells Function in CMV+ Colorectal Cancer Patients Compared to Healthy Controls

2019 ◽  
Author(s):  
Mona Shaker Ardakani ◽  
Fatemeh Pak ◽  
Parviz Kokhaei ◽  
Mohammad Sadegh Fazeli ◽  
Yadollah Shakiba ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Healthy Individuals ◽  
T Cell Therapy ◽  
Peptide Epitopes ◽  
Tumor Tissues ◽  
Tnf Α ◽  
Ifn Γ

The oncogenic role of human cytomegalovirus (HCMV) has been recently shown in different cancers like colorectal cancer (CRC). According to the recent immunotherapy approach to target the CMV-expressing tumor cells, we investigated the CMV peptide-stimulated CD8+T cells functions in CRC patients compared to healthy individuals. All sixteen patients and seven controls were CMV seropositive. Blood samples were obtained from patients without chemotherapy and radiotherapy before surgery. Cytotoxic CD8+ T cells were generated using 14-day culture of PBMCs in the presences of CMV peptide epitopes and rhIL-2. In addition to the supernatant evaluations for TNF-α and IFN-γ, the functionality of CD8+ T cells was examined by detecting CD107a and intracellular IFN-γ using flow cytometry. CMV DNA was detected in tissues by Real Time PCR. CMV DNA was found in 31% of tumor tissues, while it was not seen in the adjacent non-tumor tissues. There was a close association between CMV in tumor tissue and tumor grade. Surface expression of CD107a and intracellular IFN-γ in CMV-stimulated CD8+T cells and the level of IFN-γ production in patient and control groups increased significantly after culture. The number of functions increased in patients (p<0.05) and healthy individuals after culture. Followingstimulation, expressions of CD107a and intracellular IFN-γ were elevated in tumor CMV positive patients while the TNF-α secretion was decreased. In vitro stimulation of PBMC in the presence of CMV peptide epitopes and IL-2 can be an applicable method to generate cytotoxic CD8+ T cells in CRC patients for future T cell therapy.

scholarly journals MUC4 mutation correlates with tumor mutation burden and the immune microenvironment in colorectal cancer

2020 ◽  
Author(s):  
Ting Li ◽  
Wenjia Hui ◽  
Halina Halike ◽  
Feng Gao
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Gene Mutations ◽  
Cancer Genome ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8 T cells, activated NK cells, M1 macrophages and resting memory CD4 T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

Correlation between driver mutation and immune microenvironment in colorectal cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15513-e15513
Author(s):  
Xiaochen Cai ◽  
Yuezong Bai ◽  
Xiaochen Zhao ◽  
Longgang Cui ◽  
Hui Chen
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Nk Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Tumor Stroma ◽  
Wild Type ◽  
Colorectal Cancer Patients

e15513 Background: Immune checkpoint inhibitor (ICI) therapy has made great achievements, but ICI monotherapies show less effectiveness in colorectal cancer patients. Biomarker exploration have carried out from PD-L1 expression, neo-antigen, gene mutation, etc., but no satisfactory results have been obtained. Methods: Patients, Colorectal cancer patients. Methods, Multi-color immunohistochemistry (multi-IHC) was used to evaluate CD8+ T cells, macrophages and natural killer cell (NK cell) in tumors and tumor stroma. The Shapiro-Wilk method was used to test the normality of the data, and the t-test or Mann-Whitney U test was used according to the test results. A two-sided P < 0.05 was considered a significant difference. Results: The study included 72 colorectal cancer patients, including 26 female (36.7%) and 46 male (63.8%), with a median age of 59.5 (50-67.3). There were 6 patients (8.3%) with BRAF mutation, 43 patients (59.7%) with KRAS mutation, and 56 patients (77.8%) with TP53 mutation. The results of immunohistochemistry showed that, BRAF mutation Vs BRAF wild-type or KRAS mutation Vs KRAS wild-type, the number or proportion of CD8+ T cells, macrophages or NK cells in tumor and tumor stroma were not statistically different. For TP53 mutation Vs TP53 wild-type, the number and proportion of CD8+ T cells or macrophages in tumor and tumor stroma were not statistically different. There was no statistical difference in the number and proportion of NK cells in tumor. But, the median number of NK cells in tumor stroma was 345 Vs 129, p = 0.06, and the proportion of NK cells was 5.2% Vs 1.39%, p = 0.02. Conclusions: There is no significant change in the immune microenvironment of colorectal cancer patients with BRAF mutation and KRAS mutation. There are more NK cells in tumor stroma of colorectal cancer patients with TP3 mutation.

scholarly journals Prognostic Biomarker MUC4 Mutations in Colon Adenocarcinoma Correlating with Tumor Microenvironment

2021 ◽  
Author(s):  
Ting Li ◽  
Wenjia Hui ◽  
Feng Gao
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Killer Cell ◽  
Gene Mutations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8+ T cells, activated NK cells, M1 macrophages and resting memory CD4+ T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals A reassessment of the role of B7-1 expression in tumor rejection.

1995 ◽  
Vol 182 (5) ◽  
pp. 1415-1421 ◽  
Author(s):  
T C Wu ◽  
A Y Huang ◽  
E M Jaffee ◽  
H I Levitsky ◽  
D M Pardoll
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Tumor Rejection ◽  
Type B ◽  
Wild Type ◽  
Systemic Immunity ◽  
Murine Tumor

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.

scholarly journals Aberrant Regulation of Hematopoiesis by T Cells in BAZF-Deficient Mice

2007 ◽  
Vol 27 (15) ◽  
pp. 5275-5285 ◽  
Author(s):  
Hal E. Broxmeyer ◽  
Sarita Sehra ◽  
Scott Cooper ◽  
Lisa M. Toney ◽  
Saritha Kusam ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Physiological Role ◽  
Normal Function ◽  
Wild Type ◽  
Indirect Pathway ◽  
Hematopoietic Progenitor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Deficient Mice

ABSTRACTThe BAZF (BCL-6b) protein is highly similar to the BCL-6 transcriptional repressor. While BCL-6 has been characterized extensively, relatively little is known about the normal function of BAZF. In order to understand the physiological role of BAZF, we created BAZF-deficient mice. Unlike BCL-6-deficient mice, BAZF-deficient mice are healthy and normal in size. However, BAZF-deficient mice have a hematopoietic progenitor phenotype that is almost identical to that of BCL-6-deficient mice. Compared to wild-type mice, both BAZF-deficient and BCL-6-deficient mice have greatly reduced numbers of cycling hematopoietic progenitor cells (HPC) in the BM and greatly increased numbers of cycling HPC in the spleen. In contrast to HPC from wild-type mice, HPC from BAZF-deficient and BCL-6-deficient mice are resistant to chemokine-induced myelosuppression and do not show a synergistic growth response to granulocyte-macrophage colony-stimulating factor plus stem cell factor. Depletion of CD8 T cells in BAZF-deficient mice reverses several of the hematopoietic defects in these mice. Since both BAZF- and BCL-6-deficient mice have defects in CD8 T-cell differentiation, we hypothesize that both BCL-6 and BAZF regulate HPC homeostasis by an indirect pathway involving CD8 T cells.

scholarly journals CCL5-deficiency enhances intratumoral infiltration of CD8+ T cells in colorectal cancer

2018 ◽  
Vol 9 (7) ◽  
Author(s):  
Shengbo Zhang ◽  
Ming Zhong ◽  
Chao Wang ◽  
Yanjie Xu ◽  
Wei-Qiang Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cd8 T Cells
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