The chemokine monocyte chemoattractant protein-1/CCL2 is a promoter of breast cancer metastasis

Breast cancer is the most prevalent cancer worldwide, and metastasis is the leading cause of death in cancer patients. Human monocyte chemoattractant protein-1 (MCP-1/CCL2) was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes. MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages (TAMs), and it became a candidate target of clinical intervention; however, the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1. The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues, including breast cancers. Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established. The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung, bone, and brain was examined in mouse breast cancer models. The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone. Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported. In the present manuscript, we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis

ID4-dependent reprogramming of tumor associated macrophages in triple negative breast cancer

Breast cancer is one of the most common cancer affecting especially women worldwide and it shows a particularly aggressive behavior in the triple negative (TNBC) and basal-like breast cancer (BLBC) subtypes that are characterized by poor prognosis and by the lack of targeted therapies. Moreover, it is well established that the presence of a massive leukocyte infiltrate, is involved in the promotion of tumor progression, contributing in particular to the angiogenic switch that occurs in the early phases of tumor progression. Among the variety of cells infiltrating breast tumors, macrophages have been extensively shown to tightly control the angiogenic onset and progression to malignancy. Here, we investigated whether ID4 protein, previously reported to enhance the angiogenic potential of breast cancer cells, exerts its function also modulating the activity of tumor-associated macrophages. We first assessed the significant association between the expression of ID4 and the macrophages marker CD68 in series of triple negative breast tumors. Of note, high ID4 mRNA expression in presence of a high macrophage infiltrate (determined as the expression of 8 macrophage markers) in BLBC is a strong predictor of poor survival. In vitro and in vivo migration assays evidenced that expression of ID4 in breast cancer cells is able to influence macrophages motility. At gene expression level we observed induction of ID4 itself, in macrophages co-cultured with breast cancer cells, induction that was impaired when breast cancer cells were depleted of ID4 expression. The same ID4-dependent behavior was observed for HIF-1A and for an angiogenesis-related signature in macrophages. Expression of angiogenesis-related genes was further controlled by miR-107, down-regulated in macrophages in ID4-dependent manner. Altogether our results highlight a key role for ID4 in dictating the angiogenic behavior of tumor-associated macrophages in breast cancer

Biomarker Discovery with Quantum Neural Networks: A Case-study in CTLA4-Activation Pathways

Biomarker discovery is a challenging task due to the massive search space. Quantum computing and quantum Artificial Intelligence (quantum AI) can be used to address the computational problem of biomarker discovery tasks. We propose a Quantum Neural Networks (QNNs) architecture to discover biomarkers for input activation pathways. The Maximum Relevance, Minimum Redundancy (mRMR) criteria is used to score biomarker candidate sets. Our proposed model is economical since the neural solution can be delivered on constrained hardware. We demonstrate the proof of concept on four activation pathways associated with CTLA4, including (1) CTLA4-activation stand-alone, (2) CTLA4-CD8A-CD8B co-activation, (3) CTLA4-CD2 co-activation, and (4) CTLA4-CD2-CD48-CD53-CD58-CD84 co-activation. The model indicates new biomarkers associated with the mutational activation of CLTA4-associated pathways, including 20 genes: CLIC4, CPE, ETS2, FAM107A, GPR116, HYOU1, LCN2, MACF1, MT1G, NAPA, NDUFS5, PAK1, PFN1, PGAP3, PPM1G, PSMD8, RNF213, SLC25A3, UBA1, and WLS. We open source the implementation at: https://github.com/namnguyen0510/Biomarker-Discovery-with-Quantum-Neural-Networks

Cytokine Landscape in Central Nervous System Metastases.

peer reviewedThe central nervous system is the location of metastases in more than 40% of patients with lung cancer, breast cancer and melanoma. These metastases are associated with one of the poorest prognoses in advanced cancer patients, mainly due to the lack of effective treatments. In this review, we explore the involvement of cytokines, including interleukins and chemokines, during the development of brain and leptomeningeal metastases from the epithelial-to-mesenchymal cell transition and blood-brain barrier extravasation to the interaction between cancer cells and cells from the brain microenvironment, including astrocytes and microglia. Furthermore, the role of the gut-brain axis on cytokine release during this process will also be addressed

Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion

Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the soluble forms thereof (e.g., PD-1, TIM-3, LAG-3, PD-L1, PD-L2 and others) in humanized tumor mice (HTM) simultaneously harboring cell line-derived (JIMT-1, MDA-MB-231, MCF-7) or patient-derived breast cancer and a functional human immune system. We identified tumor-infiltrating T cells with a triple-positive PD-1, LAG-3 and TIM-3 phenotype. While PD-1 expression was increased in both the CD4 and CD8 T cells, TIM-3 was found to be upregulated particularly in the cytotoxic T cells in the MDA-MB-231-based HTM model. High levels of soluble TIM-3 and galectin-9 (a TIM-3 ligand) were detected in the serum. Surprisingly, soluble PD-L2, but only low levels of sPD-L1, were found in mice harboring PD-L1-positive tumors. Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2+ and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape

The current advances of lncRNAs in breast cancer immunobiology research

Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related death in women worldwide. Breast cancer development and progression are mainly associated with tumor-intrinsic alterations in diverse genes and signaling pathways and with tumor-extrinsic dysregulations linked to the tumor immune microenvironment. Significantly, abnormal expression of lncRNAs affects the tumor immune microenvironment characteristics and modulates the behavior of different cancer types, including breast cancer. In this review, we provide the current advances about the role of lncRNAs as tumor-intrinsic and tumor-extrinsic modulators of the antitumoral immune response and the immune microenvironment in breast cancer, as well as lncRNAs which are potential biomarkers of tumor immune microenvironment and clinicopathological characteristics in patients, suggesting that lncRNAs are potential targets for immunotherapy in breast cancer

The Combination of Immune Checkpoint Blockade with Tumor Vessel Normalization as a Promising Therapeutic Strategy for Breast Cancer: An Overview of Preclinical and Clinical Studies

Immune checkpoint inhibitors (ICIs) have a modest clinical activity when administered as monotherapy against breast cancer (BC), the most common malignancy in women. Novel combinatorial strategies are currently being investigated to overcome resistance to ICIs and promote antitumor immune responses in a greater proportion of BC patients. Recent studies have shown that the BC abnormal vasculature is associated with immune suppression in patients, and hampers both drug delivery and immune effector cell trafficking to tumor nests. Thus, strategies directed at normalizing (i.e., at remodeling and stabilizing) the immature, abnormal tumor vessels are receiving much attention. In particular, the combination of ICIs with tumor vessel normalizing agents is thought to hold great promise for the treatment of BC patients. Indeed, a compelling body of evidence indicates that the addition of low doses of antiangiogenic drugs to ICIs substantially improves antitumor immunity. In this review, we outline the impact that the reciprocal interactions occurring between tumor angiogenesis and immune cells have on the immune evasion and clinical progression of BC. In addition, we overview preclinical and clinical studies that are presently evaluating the therapeutic effectiveness of combining ICIs with antiangiogenic drugs in BC patients

The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers

Càncer de mama; Genòmica del càncer; Biomarcadors tumoralsCáncer de mama; Genómica del cáncer; Biomarcadores tumoralesBreast cancer; Cancer genomics; Tumour biomarkersThe biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.This work was supported by Cancer Research UK. L.D.M.A. was partly funded by Spanish Association against cancer

Liquid Biopsies to Occult Brain Metastasis

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the uniquely distinct brain microenvironment. Keeping abreast with the recent breakthroughs in the context of various biomolecules detections and identifications, the circulating tumor cells (CTC), cell-free nucleotides, non-coding RNAs, secretory proteins, and metabolites can be pursued in human body fluids such as blood, serum, cerebrospinal fluid (CSF), and urine to obtain potential candidates for biomarker development. The liquid biopsy-based biomarkers can overlay with current imaging techniques to amplify the signal viable for improving the early detection and treatments of occult BrM

Tumor NOS2 and COX2 spatial juxtaposition with CD8+ T cells promote metastatic and cancer stem cell niches that lead to poor outcome in ER− breast cancer

Estrogen receptor-negative breast cancer is an aggressive subtype with limited therapeutic options. Elevated nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) mediates immunosuppression and poor survival in these tumors. Therefore, the influence of tumor NOS2/COX2 on immune architecture was examined in 16 African American and 5 Caucasian ER- tumors. Elevated tumor NOS2/COX2 limited CD8+ T cell infiltration at 5-yr survival. Distinct CD8+/-NOS2+/-COX2+/- phenotypes defining metastatic and cancer stem cell niches, and immune desert regions were identified. These results were supported by an unbiased, unsupervised nonlinear dimensionality-reduction UMAP technique incorporating spatial relations between cells and validated in a separate gene expression cohort using NOS2/CD8 and COX2/CD8 ratios. Additionally, elongated tumor cells were specifically in CD8-NOS2+COX2+ regions, suggesting metastatic hot spots. This work demonstrates predictive power of spatial analyses of CD8/NOS2/COX2 architecture and supports the use of clinically available NOS2/COX2 inhibitors for improved survival in patients with these aggressive tumors