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Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.

ABSTRACT: The tumor microenvironment is composed of many immune cell subpopulations and is an important factor in the malignant progression of neoplasms, particularly breast cancer (BC). However, the cytokine networks that coordinate various regulatory events within the BC interstitium remain largely uncharacterized. Moreover, the data obtained regarding the origin of cytokine secretions, the levels of secretion associated with tumor development, and the possible clinical relevance of cytokines remain controversial. Therefore, we profiled 27 cytokines in 78 breast tumor interstitial fluid (TIF) samples, 43 normal interstitial fluid (NIF) samples, and 25 matched serum samples obtained from BC patients with Luminex xMAP multiplex technology. Eleven cytokines exhibited significantly higher levels in the TIF samples compared with the NIF samples: interleukin (IL)-7, IL-10, fibroblast growth factor-2, IL-13, interferon (IFN)?-inducible protein (IP-10), IL-1 receptor antagonist (IL-1RA), platelet-derived growth factor (PDGF)-?, IL-1?, chemokine ligand 5 (RANTES), vascular endothelial growth factor, and IL-12. An immunohistochemical analysis further demonstrated that IL-1RA, IP-10, IL-10, PDGF-?, RANTES, and VEGF are widely expressed by both cancer cells and tumor-infiltrating lymphocytes (TILs), whereas IP-10 and RANTES were preferentially abundant in triple-negative breast cancers (TNBCs) compared to Luminal A subtype cancers. The latter observation corresponds with the high level of TILs in the TNBC samples. IL-1?, IL-7, IL-10, and PDGF? also exhibited a correlation between the TIF samples and matched sera. In a survival analysis, high levels of IL-5, a hallmark TH2 cytokine, in the TIF samples were associated with a worse prognosis. These findings have important implications for BC immunotherapy research.

SUBMITTER: Espinoza JA

PROVIDER: S-EPMC5215081 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.

Espinoza Jaime A JA Jabeen Shakila S Batra Richa R Papaleo Elena E Haakensen Vilde V Timmermans Wielenga Vera V Møller Talman Maj-Lis ML Brunner Nils N Børresen-Dale Anne-Lise AL Gromov Pavel P Helland Åslaug Å Kristensen Vessela N VN Gromova Irina I

Oncoimmunology 20161024 12

The tumor microenvironment is composed of many immune cell subpopulations and is an important factor in the malignant progression of neoplasms, particularly breast cancer (BC). However, the cytokine networks that coordinate various regulatory events within the BC interstitium remain largely uncharacterized. Moreover, the data obtained regarding the origin of cytokine secretions, the levels of secretion associated with tumor development, and the possible clinical relevance of cytokines remain con ...[more]

PMID: 28123884

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Project description:BackgroundStudies on tumor-secreted microRNAs point to a functional role of these in cellular communication and reprogramming of the tumor microenvironment. Uptake of tumor-secreted microRNAs by neighboring cells may result in the silencing of mRNA targets and, in turn, modulation of the transcriptome. Studying miRNAs externalized from tumors could improve cancer patient diagnosis and disease monitoring and help to pinpoint which miRNA-gene interactions are central for tumor properties such as invasiveness and metastasis.MethodsUsing a bioinformatics approach, we analyzed the profiles of secreted tumor and normal interstitial fluid (IF) microRNAs, from women with breast cancer (BC). We carried out differential abundance analysis (DAA), to obtain miRNAs, which were enriched or depleted in IFs, from patients with different clinical traits. Subsequently, miRNA family enrichment analysis was performed to assess whether any families were over-represented in the specific sets. We identified dysregulated genes in tumor tissues from the same cohort of patients and constructed weighted gene co-expression networks, to extract sets of co-expressed genes and co-abundant miRNAs. Lastly, we integrated miRNAs and mRNAs to obtain interaction networks and supported our findings using prediction tools and cancer gene databases.ResultsNetwork analysis showed co-expressed genes and miRNA regulators, associated with tumor lymphocyte infiltration. All of the genes were involved in immune system processes, and many had previously been associated with cancer immunity. A subset of these, BTLA, CXCL13, IL7R, LAMP3, and LTB, was linked to the presence of tertiary lymphoid structures and high endothelial venules within tumors. Co-abundant tumor interstitial fluid miRNAs within this network, including miR-146a and miR-494, were annotated as negative regulators of immune-stimulatory responses. One co-expression network encompassed differences between BC subtypes. Genes differentially co-expressed between luminal B and triple-negative breast cancer (TNBC) were connected with sphingolipid metabolism and predicted to be co-regulated by miR-23a. Co-expressed genes and TIF miRNAs associated with tumor grade were BTRC, CHST1, miR-10a/b, miR-107, miR-301a, and miR-454.ConclusionIntegration of IF miRNAs and mRNAs unveiled networks associated with patient clinicopathological traits, and underlined molecular mechanisms, specific to BC sub-groups. Our results highlight the benefits of an integrative approach to biomarker discovery, placing secreted miRNAs within a biological context.

Project description:INTRODUCTION:The genesis of cancer appears to be a complex matter, which is not simply based upon few genetic abnormalities/alteration. In fact, irregular microvasculature and aberrant interstitium of solid tumors impose significant pathophysiologic barrier functions against cancer treatment modalities, hence novel strategies should holistically target bioelements of tumor microenvironment (TME). In this study, we provide some overview and insights on TME and important strategies used to control the impacts of such pathophysiologic barriers. METHODS:We reviewed all relevant literature for the impacts of tumor interstitium and microvasculature within the TME as well as the significance of the implemented strategies. RESULTS:While tumorigenesis initiation seems to be in close relation with an emergence of hypoxia and alterations in epigenetic/genetic materials, large panoplies of molecular events emerge as intricate networks during oncogenesis to form unique lenient TME in favor of tumor progression. Within such irregular interstitium, immune system displays defective surveillance functionalities against malignant cells. Solid tumors show multifacial traits with coadaptation and self-regulation potentials, which bestow profound resistance against the currently used conventional chemotherapy and immunotherapy agents that target solely one face of the disease. CONCLUSION:The cancerous cells attain unique abilities to form its permissive microenvironment, wherein (a) extracellular pH is dysregulated towards acidification, (b) extracellular matrix (ECM) is deformed, (c) stromal cells are cooperative with cancer cells, (d) immune system mechanisms are defective, (e) non-integrated irregular microvasculature with pores (120-1200 nm) are formed, and (h) interstitial fluid pressure is high. All these phenomena are against cancer treatment modalities. As a result, to control such abnormal pathophysiologic traits, novel cancer therapy strategies need to be devised using multifunctional nanomedicines and theranostics.

Project description:To explore lymphocyte infiltration as a potential mechanism behind CXCL14-mediated tumor growth suppression in oral cavity squamous cell carcinoma (OSCC). We analyzed single cell RNA-sequencing (scRNA-seq) data from OSCC to identify expression changes among malignant cells in lymph nodes (LN) versus primary tumors. CXCL14 expression in murine OSCC cell lines was quantified using qRT-PCR. Short hairpin RNA knockdown of CXCL14 was performed in mouse oral cavity (MOC)1 cells, and CXCL14 overexpression was performed in MOC2 cells. Cells in each condition were injected into C57BL/6 mice with and without T cell depletion, and tumor volume was measured. At 30 days, tumors were dissociated and analyzed by flow cytometry for CD45+CD3+ T cells. CXCL14 expression was correlated with gene expression signatures of tumor infiltrating lymphocytes (TIL) in scRNA-seq data, as well as TCGA tumors. scRNA-seq revealed CXCL14 as the most significantly downregulated gene among malignant cells in LNs relative to primary tumor, supporting a role in preventing invasion and/or metastasis. In a murine immunocompetent model, CXCL14 expression was higher in indolent MOC1 cells than in more aggressive MOC2 cells. Tumor growth in vivo was significantly increased by CXCL14 knockdown in MOC1 cells relative to control, with a corresponding decrease in TIL. In MOC2 cells, tumor growth was significantly reduced by CXCL14 overexpression relative to control and TIL were increased. Both effects were lost with T cell depletion. In a human tumor scRNA-seq cohort, we found that only malignant cell CXCL14, but not non-malignant cell or fibroblast CXCL14, was associated with TIL. Bulk CXCL14 from the TCGA cohort had no association with TIL. Higher CXCL14 expression by tumor cells is associated with reduced tumor growth and increased TIL, supporting immune-mediated suppression of tumor growth in OSCC. Given that CXCL14 is downregulated in LN metastases compared with primary tumors, our data raise the possibility that CXCL14-mediated immune infiltration may discourage invasion and metastasis. In human scRNA-seq data, only malignant cell-specific CXCL14 was associated with TIL, suggesting a critical context-dependent effect of CXCL14 expression.

Dataset Information

Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.

Publications

Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.

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