Characterisation of the immune contexture of breast cancer subtypes

Purpose: The purpose and aim of this project was to investigate immune contexture according to tumour molecular subtype, and ER status. To find the interrelationship between serum cytokine levels and specific tumour cell infiltration levels. Material and methods: A newly released deconvolution tool called xCell, uses gene expression data to identify 64 different cell types present in the bulk tissue assessed for gene expression. We first validated the method by comparing xCell´s output with immune cell infiltration assessed by immunohistochemistry staining. The xCell profiles were then compared between the breast cancer molecular subtypes and ER status, to identify differences in the microenvironment. 26 immune cell profiles were compared to serum cytokine levels to find potential correlation between cell type levels and cytokine levels. Results: The findings suggest clear differences of levels of immune cells in the different subtypes and ER status. ER negative samples have higher immune infiltration compared to ER positive samples. Luminal A have higher level of epithelial cells and stroma cell when compared to the other subtypes. The Luminal B has higher immune infiltration of helper T cells and higher immune infiltration when compared to Luminal A and Normal-like. The Normal-like subtype has higher levels of stem cell like cells. Her2-enriched and the Basal-like subtype have the largest amount of immune infiltration compared to the other subtypes. When correlating immune cell levels to cytokine levels, we found that levels of PDGF-bb corelate to higher levels of B cells which may reflect lymphangiogenesis. Conclusion: These findings suggest that there are differences in the microenvironment of breast cancer subtypes. The method used to identify these findings should be better validated, as it only validates a small fraction of the cell types. In the future, a large validation using more markers, should be used. By further analysing the cell levels and infiltration profiles for individual subtypes, we could better understand the differences in the environment within a subtype. PDGF cytokine may be a good candidate for immunotherapy. These findings could potentially have prognostic and/or predictive value to deliver more targeted treatments

Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics.

Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines – the molecules coordinating and fine-tuning immune response – are still poorly characterized. Using two breast cancer cohorts (MicMa, n = 131, DCTB, n = 28) and the multiplex Luminex platform, we measured the levels of 27 cytokines in the serum of breast cancer patients prior to treatment. We investigated the cytokine levels in relation to clinicopathological characteristics and in perspective of the tumor infiltrating immune cells predicted from the bulk mRNA expression data. Unsupervised clustering analysis of the serum cytokine levels in the MicMa cohort identified a cluster of pro-inflammatory, pro-angiogenic, and Th2-related cytokines which was associated with poor prognosis. Notably high levels of platelet derived growth factor BB (PDGF) reflected a more aggressive tumor phenotype and larger tumor size. A significant positive correlation between serum levels of interferon gamma-induced protein 10 (IP10) and its mRNA expression at the tumor site suggested that tumor-IP10-production may outflow to the bloodstream. High IP10 serum levels were associated with a worse prognosis. Finally, we found serum levels of both PDGF and IP10 associated with enrichment scores of specific tumor infiltrating immune cells. Our study suggests that monitoring cytokine circulating levels in breast cancer could be used to characterize breast cancers and the immune composition of their microenvironment through readily available biological material

Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics

Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines – the molecules coordinating and fine-tuning immune response – are still poorly characterized. Using two breast cancer cohorts (MicMa, n = 131, DCTB, n = 28) and the multiplex Luminex platform, we measured the levels of 27 cytokines in the serum of breast cancer patients prior to treatment. We investigated the cytokine levels in relation to clinicopathological characteristics and in perspective of the tumor infiltrating immune cells predicted from the bulk mRNA expression data. Unsupervised clustering analysis of the serum cytokine levels in the MicMa cohort identified a cluster of pro-inflammatory, pro-angiogenic, and Th2-related cytokines which was associated with poor prognosis. Notably high levels of platelet derived growth factor BB (PDGF) reflected a more aggressive tumor phenotype and larger tumor size. A significant positive correlation between serum levels of interferon gamma-induced protein 10 (IP10) and its mRNA expression at the tumor site suggested that tumor-IP10-production may outflow to the bloodstream. High IP10 serum levels were associated with a worse prognosis. Finally, we found serum levels of both PDGF and IP10 associated with enrichment scores of specific tumor infiltrating immune cells. Our study suggests that monitoring cytokine circulating levels in breast cancer could be used to characterize breast cancers and the immune composition of their microenvironment through readily available biological material. KEYWORDS: Breast cancer, cytokines, pathological markers, immune response, prognosi