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Epstein-Barr Virus+ B Cells in the Breast Cancer Immune Response: A Case Report.

ABSTRACT: Tumor-Infiltrating Lymphocytes (TILs) are composed by several immune subpopulations including NK, NKT, Tab, Tgd and B cells. Although some of these cells can have antitumoral activities, there is also a large number of cells which are not tumor-specific,known as bystander cells. These cells may not have a direct role in the antitumoral response but could lead to a modulation of the immune response after time. Recent studies have described fatal encephalitis and myocarditis in cancer patients after immune checkpoint therapies, in which EBV-specific T cells may be involved. Since EBV is able to infect B cells and epithelial cells, both present in the primary tumor site, the first events of these fatal responses could be a consequence of a dysregulation of the immune system in the tumor microenvironment, although this have not been deeply studied. Thus, the main objectives of this study are (i) to use EBV-transformed B cells from the tumor site as a model to study the tumor-infiltrating EBV+ B cells and (ii) to use these EBV-derived B cells to study the relationship with autologous T cells isolated from the tumor site. T cells from TILs have been isolated from a triple negative breast cancer patient before neoadjuvancy and were expanded directly from the biopsy. A Patient-Derived Xenograft (PDX) generated from the breast tumor, progressed into a lymphocytic neoplasm. EBVtransformed B cells were obtained from this PDX (PDX-derived B cells). T Cell Receptor high-throughput sequencing has been used to monitor the clonotypes present in the different samples. We have found 43 clonotypes infiltrating the PDX-562 tissue and 18 of them were also present in the human biopsy or in the biopsy-derived T cell cultures. 5 of these sequences were found in one of the biopsy-derived T cells analyzed. Thus, PDXderived B cells have been used as antigen presenting cells to expand these cells. Few clonotypes were obtained after expansions, although the analysis of the middle CDR3 have revealed a similar pattern with the 18 sequences from the PDX sample. Furthermore, peptides presented by HLA have been eluted from PDX-derived B cells, followed by MS analysis. Peptides obtained derived from 31 different proteins and >40% are cancerrelated in terms of expression.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, B-lymphoblastoma Cell

DISEASE(S): Breast Cancer

SUBMITTER: Montserrat Carrascal

LAB HEAD: Mercè Martí

PROVIDER: PXD028646 | Pride | 2021-11-17

REPOSITORIES: Pride

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			Action	DRS
	Multiconsensus_from_7_Reports_PDX_peptides.xlsx	Xlsx
	Multiconsensus_from_7_Reports_proteins_PDX.xlsx	Xlsx
	PDX_Multiconsensus_from_2_Reports_human_EpsteinBarr_peptides.xlsx	Xlsx
	PDX_Multiconsensus_from_2_Reports_human_EpsteinBarr_proteins.xlsx	Xlsx
	PDX_claseI_Fr25_20210519_01.raw	Raw

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Project description:The better prognosis of patients with Epstein-Barr virus-positive gastric carcinoma than those with EBV-negative GC is correlated with the degree of recruitment of inflammatory tumor infiltrating cells (TIL) to the vicinity of tumor cells. We hypothesized that the better prognosis would associate with less genetic or epigenetic alterations in EBV(+)GC, or EBV infection should deregulate immune modulator proteins, of which secretion recruit TIL. Therefore we performed mRNA expression profilings in EBV(-)GC and EBV(+)GC, each of which was pair wise compared with their normal control. We found that EBV(+)GC had much more molecular homogeneity with focused alterations in immune modulator genes; The Pearson correlation matrix analyses demonstrated that EBV(+)GC tumor showed remarkably high tumor homogeneity. While EBV(-)GC had considerable number genes that are differentially expressed genes from their normal counterparts, EBV(+)GC showed only a handful, almost 20 fold less number of DEG than EBV(-)GC under the same p value cutoff (p<0.001). Gene ontology and pathway analyses showed that while pathways of cation homeostasis, digestion and ion transport were commonly deregulated in both GC types, genes for chromatin assembly, prostaglandin receptor activity, pattern specification process are selectively deregulated in EBV(-)GC tumors. In contrast, pathways or genes for cytokine activity, immune response and lipoprotein particle clearance are selectively deregulated in EBV(+)GC tumors. These results demonstrate that EBV(+)GC inherently evolves to high homogeneity with fewer changes in gene expression and these secret immune modulatory chemokines could recruit reactive immune cells to EBV(+)GC, leading to favorable microenvironment for cancer suppression. All patients underwent the surgery for advanced gastric carcinoma (GC) except one patient with early GC. The EBV-presence in the GC was verified by in situ EBV-encoded small RNA (ERER) staining.. The 14 paired EBV(-)GC patients and 12 paired EBV(+)GC patients were selected for this study. Tumor tissue (T)and normal tissues (N) from distant sites from tumor areas were dissected, frozen at -80C and were subjected to RNA purification, mRNA array profiling analyses.

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Epstein-Barr Virus+ B Cells in the Breast Cancer Immune Response: A Case Report.

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