scholarly journals High WHSC1L1 Expression Reduces Survival Rates in Operated Breast Cancer Patients with Decreased CD8+ T Cells: Machine Learning Approach

2021 ◽  
Vol 11 (7) ◽  
pp. 636
Author(s):  
Hyung-Suk Kim ◽  
Kyueng-Whan Min ◽  
Dong-Hoon Kim ◽  
Byoung-Kwan Son ◽  
Mi-Jung Kwon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Survival Rates ◽  
Gradient Boosting ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Cancer Pathogenesis ◽  
Pathway Networks

Nuclear receptor-binding SET domain protein (NSD), a histone methyltransferase, is known to play an important role in cancer pathogenesis. The WHSC1L1 (Wolf-Hirschhorn syndrome candidate 1-like 1) gene, encoding NSD3, is highly expressed in breast cancer, but its role in the development of breast cancer is still unknown. The purpose of this study was to analyze the survival rates and immune responses of breast cancer patients with high WHSC1L1 expression and to validate the results using gradient boosting machine (GBM) in breast cancer. We investigated the clinicopathologic parameters, proportions of immune cells, pathway networks and in vitro drug responses according to WHSC1L1 expression in 456, 1500 and 776 breast cancer patients from the Hanyang University Guri Hospital, METABRIC and TCGA, respectively. High WHSC1L1 expression was associated with poor prognosis, decreased CD8+ T cells and high CD274 expression (encoding PD-L1). In the pathway networks, WHSC1L1 was indirectly linked to the regulation of the lymphocyte apoptotic process. The GBM model with WHSC1L1 showed improved prognostic performance compared with the model without WHSC1L1. We found that VX-11e, CZC24832, LY2109761, oxaliplatin and erlotinib were effective in inhibiting breast cancer cell lines with high WHSC1L1 expression. High WHSC1L1 expression could play potential roles in the progression of breast cancer and targeting WHSC1L1 could be a potential strategy for the treatment of breast cancer.

scholarly journals Resident memory CD8+ T cells within cancer islands mediate survival in breast cancer patients

JCI Insight ◽  
2019 ◽  
Vol 4 (19) ◽  
Author(s):  
Colt A. Egelston ◽  
Christian Avalos ◽  
Travis Y. Tu ◽  
Anthony Rosario ◽  
Roger Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Breast Cancer Patients ◽  
Memory Cd8 T Cells

scholarly journals Interaction between GRP78 and IGFBP-3 Affects Tumourigenesis and Prognosis in Breast Cancer Patients

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3821
Author(s):  
Hanna A. Zielinska ◽  
Carl S. Daly ◽  
Ahmad Alghamdi ◽  
Amit Bahl ◽  
Muhammed Sohail ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Survival Rates ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Kaplan Meier ◽  
Induced Apoptosis ◽  
Igfbp 3

Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role in breast cancer progression and was recently shown to bind to the chaperone protein glucose-regulated protein 78 (GRP78); however, the clinical significance of this association remains poorly investigated. Here we report a direct correlation between the expression of GRP78 and IGFBP-3 in breast cancer cell lines and tumour sections. Kaplan–Meier survival plots revealed that patients with low GRP78 expression that are positive for IGFBP-3 had poorer survival rates than those with low IGFBP-3 levels, and we observed a similar trend in the publicly available METABRIC gene expression database. With breast cancer cells, in vitro IGFBP-3 enhanced induced apoptosis, however when GRP78 expression was silenced the actions of IGFBP-3 were switched from increasing to inhibiting ceramide (C2)-induced cell death and promoted cell invasion. Using immunofluorescence and cell surface biotinylation, we showed that knock-down of GRP78 negated the entry of IGFBP-3 into the cells. Together, our clinical and experimental results suggest that loss of GRP78 reduces IGFBP-3 entry into cells switching its actions to promote tumorigenesis and predicts a poor prognosis in breast cancer patients.

scholarly journals Intratumoral, rather than stromal, CD8+ T cells could be a potential negative prognostic marker in invasive breast cancer patients

2019 ◽  
Vol 12 (3) ◽  
pp. 585-595 ◽  
Author(s):  
Ivana Catacchio ◽  
Nicola Silvestris ◽  
Emanuela Scarpi ◽  
Laura Schirosi ◽  
Anna Scattone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Prognostic Marker ◽  
Cd8 T Cells ◽  
Invasive Breast Cancer ◽  
Breast Cancer Patients

scholarly journals Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3450
Author(s):  
Debaditya Chakraborty ◽  
Cristina Ivan ◽  
Paola Amero ◽  
Maliha Khan ◽  
Cristian Rodriguez-Aguayo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Artificial Intelligence ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Immune Cell ◽  
Survival Rates ◽  
Breast Cancer Patients ◽  
Inflection Points ◽  
Explainable Artificial Intelligence

We investigated the data-driven relationship between immune cell composition in the tumor microenvironment (TME) and the ≥5-year survival rates of breast cancer patients using explainable artificial intelligence (XAI) models. We acquired TCGA breast invasive carcinoma data from the cbioPortal and retrieved immune cell composition estimates from bulk RNA sequencing data from TIMER2.0 based on EPIC, CIBERSORT, TIMER, and xCell computational methods. Novel insights derived from our XAI model showed that B cells, CD8+ T cells, M0 macrophages, and NK T cells are the most critical TME features for enhanced prognosis of breast cancer patients. Our XAI model also revealed the inflection points of these critical TME features, above or below which ≥5-year survival rates improve. Subsequently, we ascertained the conditional probabilities of ≥5-year survival under specific conditions inferred from the inflection points. In particular, the XAI models revealed that the B cell fraction (relative to all cells in a sample) exceeding 0.025, M0 macrophage fraction (relative to the total immune cell content) below 0.05, and NK T cell and CD8+ T cell fractions (based on cancer type-specific arbitrary units) above 0.075 and 0.25, respectively, in the TME could enhance the ≥5-year survival in breast cancer patients. The findings could lead to accurate clinical predictions and enhanced immunotherapies, and to the design of innovative strategies to reprogram the breast TME.

scholarly journals 323 Systemic administration of ladiratuzumab vedotin alone or in combination with pembrolizumab results in significant immune activation in the tumor microenvironment in metastatic breast cancer patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A349-A349
Author(s):  
Lajos Pusztai ◽  
Hailing Lu ◽  
Christopher Hale ◽  
Anne Grosse-Wilde ◽  
Jennifer Specht ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Metastatic Breast ◽  
Breast Cancer Patients

BackgroundLadiratuzumab vedotin (LV) is an investigational antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 IgG1 conjugated with monomethyl auristatin E (MMAE), a microtubule-disrupting agent. LV targets LIV-1, a protein expressed by various cancers. Along with a cytotoxic effect, LV has been shown to induce immunogenic cell death (ICD) in preclinical studies. LV is currently being investigated as a monotherapy and in combination with pembrolizumab in patients with metastatic breast cancer and other solid tumors. This correlative biomarker study aims to assess the ability of LV to modulate the tumor microenvironment (TME) in breast cancer patients.MethodsIn the SGNLVA-001 trial, metastatic breast cancer patients, predominantly of the triple negative subtype (TNBC), received LV monotherapy (2.0 or 2.5 mg/kg, every 3 weeks [q3w]). In the SGNLVA-002 trial, patients with metastatic TNBC received LV (2.0 or 2.5 mg/kg, q3w) plus pembrolizumab (200 mg, q3w). To investigate the potential effect of LV or LV plus pembrolizumab on the TME, paired pre-treatment and on-treatment tumor biopsies (Cycle [C] 1 Day [D] 5 or C1D15) were collected and analyzed by RNAseq and immunohistochemistry (IHC) staining.ResultsGene expression analysis of paired biopsy TNBC samples (n=59; baseline and C1D5) showed that LV monotherapy treatment significantly induces immune response-related gene expression, MHC, co-stimulatory molecules, and PD-L1. Gene set enrichment analysis (GSEA) demonstrated enrichment of macrophage and tumor inflammation signature genes, supporting the induction of ICD and enhancement of innate immune response. Paired tumor samples from subjects treated with LV plus pembrolizumab (n=16; baseline and C1D15) showed a broader range of gene expression changes on RNAseq compared to LV monotherapy. GSEA evidenced enrichment of genes associated with cytotoxic CD8 T cells, CD4 T helper cells, dendritic cells, and macrophages, further demonstrating the induction of ICD and activation of an innate immune response. Importantly, the combination had a unique adaptive immune response induction signature. IHC analysis confirmed the increased infiltration of macrophages after LV monotherapy. The combination with pembrolizumab resulted in a further increase in macrophages and a prominent influx of CD8 T cells.ConclusionsSystemic administration of LV monotherapy resulted in immune activation in the TME and macrophage infiltration. The combination of LV plus pembrolizumab resulted in a more potent immune activation in the TME and a prominent influx of CD8 T cells in addition to macrophages. Together these results provide a rationale for the continued clinical investigation of LV alone or in combination with pembrolizumab.Trial RegistrationNCT01969643 and NCT03310957Ethics ApprovalThe study protocols for clinical trials represented in this publication were reviewed by the respective IRB/IEC at each study site and approved before trial participants were screened and enrolled.ConsentNot applicable.

scholarly journals High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 1112
Author(s):  
Hyung Suk Kim ◽  
Byoung Kwan Son ◽  
Mi Jung Kwon ◽  
Dong-Hoon Kim ◽  
Kyueng-Whan Min
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Survival Rate ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Specific Gene ◽  
Breast Cancer Patients ◽  
Gene Sets

Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epigenetic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze survival, genetic interaction networks and anticancer immune responses in breast cancer patients with high KDM1A expression and to explore candidate target drugs. Methods: We investigated clinicopathologic parameters, specific gene sets, immunologic relevance, pathway-based networks and in vitro drug response according to KDM1A expression in 456 and 789 breast cancer patients from the Hanyang university Guri Hospital (HYGH) and The Cancer Genome Atlas, respectively. Results: High KDM1A expression was associated with a low survival rate in patients with breast cancer. In analyses of immunologic gene sets, high KDM1A expression correlated with low immune responses. In silico flow cytometry results revealed low abundances of CD8+T cells and high programmed death-ligand 1 (PD-L1) expression in those with high KDM1A expression. High KDM1A expression was associated with a decrease in the anticancer immune response in breast cancer. In pathway-based networks, KDM1A was linked directly to pathways related to the androgen receptor signaling pathway and indirectly to the immune pathway and cell cycle. We found that alisertib effectively inhibited breast cancer cell lines with high KDM1A expression. Conclusions: Strategies utilizing KDM1A may contribute to better clinical management/research for patients with breast cancer.

scholarly journals Oligoclonality of CD8+ T Cells in Breast Cancer Patients

1997 ◽  
Vol 3 (12) ◽  
pp. 836-851 ◽  
Author(s):  
Koichi Ito ◽  
James Fetten ◽  
Houman Khalili ◽  
Steven Hajdu ◽  
Erna Busch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Breast Cancer Patients

scholarly journals Quantification of Immune Variables from Liquid Biopsy in Breast Cancer Patients Links Vδ2+ γδ T Cell Alterations with Lymph Node Invasion

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 441
Author(s):  
Stéphane Fattori ◽  
Laurent Gorvel ◽  
Samuel Granjeaud ◽  
Philippe Rochigneux ◽  
Marie-Sarah Rouvière ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Breast Cancer Patients ◽  
Cancer Pathogenesis

The rationale for therapeutic targeting of Vδ2+ γδ T cells in breast cancer is strongly supported by in vitro and murine preclinical investigations, characterizing them as potent breast tumor cell killers and source of Th1-related cytokines, backing cytotoxic αβ T cells. Nonetheless, insights regarding Vδ2+ γδ T cell phenotypic alterations in human breast cancers are still lacking. This paucity of information is partly due to the challenging scarcity of these cells in surgical specimens. αβ T cell phenotypic alterations occurring in the tumor bed are detectable in the periphery and correlate with adverse clinical outcomes. Thus, we sought to determine through an exploratory study whether Vδ2+ γδ T cells phenotypic changes can be detected within breast cancer patients’ peripheral blood, along with association with tumor progression. By using mass cytometry, we quantified 130 immune variables from untreated breast cancer patients’ peripheral blood. Supervised analyses and dimensionality reduction algorithms evidenced circulating Vδ2+ γδ T cell phenotypic alterations already established at diagnosis. Foremost, terminally differentiated Vδ2+ γδ T cells displaying phenotypes of exhausted senescent T cells associated with lymph node involvement. Thereby, our results support Vδ2+ γδ T cells implication in breast cancer pathogenesis and progression, besides shedding light on liquid biopsies to monitor surrogate markers of tumor-infiltrating Vδ2+ γδ T cell antitumor activity.

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