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

Abstract

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.

Systemic immune mediators predict therapeutic response and tumor-infiltrating lymphocyte intensity in triple-negative breast cancer

“…This finding suggests that responding TNBC patients may have a more activated immune profile than nonresponding ones. Interestingly, our results also showed that TNBC responding patients had higher levels of IL-5 and IL-13 (p = 0.06) in the plasma (Fig 1), while previous studies have shown high serum levels of Th2 cytokines associated with worse prognosis in patients with other breast cancer subtypes (14). Other studies have indicated that tumors are capable of inducing systemic inflammation, hematopoietic tissue reprogramming and promote myeloid cell elevation by secreting cytokines and growth factors that enable disease progression (26,29).…”

“…Importantly, we observed an overall pattern in responder patients of positive correlations between TILs and inflammatory cytokines, while non-responder patients displayed negative correlations with TILs for the same cytokines (Fig 2D). TILs and cytokines were correlated in other studies involving breast cancer patients, revealing an association between higher levels of pro-inflammatory cytokines like IP-10 and RANTES and TILs, indicating that monitoring circulating cytokines could help to characterize the tumor microenvironment (14,35) and serve as predictive biomarkers.…”

“…The relationship between immune cells and immune mediators can influence the formation of an inflammatory TME and lead to a better response to therapy in a variety of cancers (13). In breast cancer, the interaction between tumor cells and Th2-related cytokines can lead to a pro-metastatic phenotype in the TME (14), and higher levels of IL-7 were correlated with worse clinical outcomes in breast cancer patients (15,16). Lower TNF-α concentrations after treatment were associated with a better response to therapy (17,18).…”

Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

“…The availability of clinicopathological information, including tumor grade, receptor status, and BC subtypes classification as well as the characterization of immune infiltration of every biopsy, allowed us to investigate the relationship between interstitial fluid miRNA levels and patient clinical features. We subsequently identified the deregulated gene targets of IF miRNAs in tumor tissues from the same cohort of patients [50]. Integration of miRNA and mRNA expression data helps to pinpoint the perturbed pathways responsible for breast cancer progression while strengthening biomarker selection by utilizing the combinatorial power of a bi-molecular expression profile.…”

CAncer bioMarker Prediction Pipeline (CAMPP) - A standardised and user-friendly framework for the analysis of quantitative biological data

“…For the testing of an array dataset, we used mRNA expression data from single-channel microarrays (Jabeen, et al, 2019). The dataset contained 80 breast tumour samples with expression quantified for ~ 15.000 mRNAs.…”