scholarly journals Identification of Breast Cancer Immune Subtypes by Analyzing Bulk Tumor and Single Cell Transcriptomes

2022 ◽  
Vol 9 ◽  
Author(s):  
Jia Yao ◽  
Shengwei Li ◽  
Xiaosheng Wang
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Single Cell ◽  
Mutation Rate ◽  
Immune Cell ◽  
Growth Factor Receptor ◽  
Intratumor Heterogeneity ◽  
Strong Immune Response ◽  
Survival Prognosis ◽  
Immune Signature

Background: The histological and molecular classification of breast cancer (BC) is being used in the clinical management of this disease. However, subtyping of BC based on the tumor immune microenvironment (TIME) remains insufficiently explored, although such investigation may provide new insights into intratumor heterogeneity in BC and potential clinical implications for BC immunotherapy.Methods: Based on the enrichment scores of 28 immune cell types, we performed clustering analysis of transcriptomic data to identify immune-specific subtypes of BC using six different datasets, including five bulk tumor datasets and one single-cell dataset. We further analyzed the molecular and clinical features of these subtypes.Results: Consistently in the six datasets, we identified three BC subtypes: BC-ImH, BC-ImM, and BC-ImL, which had high, medium, and low immune signature scores, respectively. BC-ImH displayed a significantly better survival prognosis than BC-ImL. Triple-negative BC (TNBC) and human epidermal growth factor receptor-2-positive (HER2+) BC were likely to have the highest proportion in BC-ImH and the lowest proportion in BC-ImL. In contrast, hormone receptor-positive (HR+) BC had the highest proportion in BC-ImL and the lowest proportion in BC-ImH. Furthermore, BC-ImH had the highest tumor mutation burden (TMB) and predicted neoantigens, while BC-ImL had the highest somatic copy number alteration (SCNA) scores. It is consistent with that TMB and SCNA correlate positively and negatively with anti-tumor immune response, respectively. TP53 had the highest mutation rate in BC-ImH and the lowest mutation rate in BC-ImL, supporting that TP53 mutations promote anti-tumor immune response in BC. In contrast, PIK3CA displayed the highest mutation rate in BC-ImM, while GATA3 had the highest mutation rate in BC-ImL. Besides immune pathways, many oncogenic pathways were upregulated in BC-ImH, including ErbB, MAPK, VEGF, and Wnt signaling pathways; the activities of these pathways correlated positively with immune signature scores in BC.Conclusions: The tumors with the strong immune response (“hot” tumors) have better clinical outcomes than the tumors with the weak immune response (“cold” tumors) in BC. TNBC and HER2+ BC are more immunogenic, while HR + BC is less immunogenic. Certain HER2+ or HR + BC patients could be propitious to immunotherapy in addition to TNBC.

scholarly journals Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

2020 ◽  
Author(s):  
Qiang Liu ◽  
Yihang Qi ◽  
Jie Zhai ◽  
Xiangyi Kong ◽  
Xiangyu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cell ◽  
Immune Checkpoints ◽  
Cell Populations ◽  
Potential Biomarker ◽  
The Impact

Abstract Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer. Furthermore, we estimated the landscape of relationship between LAG3 and ten types of cell populations in breast cancer. Gene ontology analysis revealed LAG3 were strongly correlated with immune response and inflammatory activities. We investigated the correlation pattern between LAG3 and immune modulators in pan-cancer, especially the synergistic role of LAG3 with other immune checkpoints members in breast cancer. Conclusions LAG3 expression was closely related to malignancy of breast cancer and might serve as a potential biomarker; LAG3 might plays an important role in regulating tumor immune microenvironment, not only T cells, but also other immune cells. More importantly, LAG3 might synergize with CTLA4, PD1/ PDL1 and other immune checkpoints, thereby lending more evidences to combination cancer immunotherapy by targeting LAG3, PD1/PDL1, and CTLA4 together.

scholarly journals Abstract 351: Alterations in immune cell signatures during breast cancer metastasis at single cell resolution

2020 ◽  
Author(s):  
Juliane Winkler ◽  
Weilun Tan ◽  
Christopher McGinnis ◽  
Zev Gartner ◽  
Spyros Darmanis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Breast Cancer Metastasis

scholarly journals Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Woosung Chung ◽  
Hye Hyeon Eum ◽  
Hae-Ock Lee ◽  
Kyung-Min Lee ◽  
Han-Byoel Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Primary Breast Cancer ◽  
Immune Cell ◽  
Rna Seq

scholarly journals Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients

2020 ◽  
Vol 10 ◽  
Author(s):  
Zhen Lin ◽  
Xianyi Meng ◽  
Jinming Wen ◽  
José María Corral ◽  
Darja Andreev ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Tyrosine Kinase ◽  
Protein Level ◽  
Immune Cell ◽  
Cox Regression ◽  
Rank Test ◽  
Intratumor Heterogeneity ◽  
Analysis Tool ◽  
Human Malignant Melanoma

BackgroundHuman malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA).MethodsClonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level.ResultsTumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011).ConclusionsHighly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response.

Evaluation of immunotherapy (I-O)-associated immune cell (IC) dynamics and PD-L1 expression using multispectral immunohistochemistry (mIHC) and single-cell hierarchical regression modeling in early-stage breast cancer (ESBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12070-e12070
Author(s):  
Katherine Sanchez ◽  
Maritza Martel ◽  
Shu-Ching Chang ◽  
Yaping Wu ◽  
Zhaoyu Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Nearest Neighbor ◽  
Immune Cell ◽  
Early Stage ◽  
Hierarchical Regression ◽  
Cytokine Therapy ◽  
Gm Csf ◽  
Multiple Regions ◽  
Pre Treatment

e12070 Background: In triple negative breast cancer (TNBC), anti-PD-L1 is associated with gains in overall survival, however only in tumors with > 1% PD-L1+ ICs. Locoregional cytokine therapy is being evaluated as a method of priming and redirecting ICs to tumors, which may increase I-O benefit particularly in PD-L1 negative tumors. We report a sensitive method of quantifying I-O-related changes in PD-L1 and ICs using mIHC and single-cell hierarchical regression, which controls for within-tumor and across-patient PD-L1/IC heterogeneity. Methods: Pre-treatment and resection tissues from a phase Ib trial of locoregional cytokines (IRX-2, n = 16 subjects) in ESBC were analyzed. IRX-2 contains immunostimulatory cytokines (GM-CSF, IL-2, IFN-α, INF-γ, and IL-12) and was injected in peri-areolar tissue, which communicates directly with tumor-draining lymphatics. Specimens were analyzed for 1) H&E stromal TILs score; 2) clinical PD-L1 IC expression (Ventana SP142, 2 blinded pathologists); and 3) mIHC (PerkinElmer Vectra). InForm software was used to obtain geospatial outputs of tumor cells (CK+) and ICs (CD3, CD8, CD163) across multiple regions of interest (mean:18; range: 9-32). Mixed-effects modeling was used to evaluate for changes in PD-L1, ICs, and IC/tumor distance metrics. Results: PD-L1 and IC quantity by mIHC was highly concordant with clinical PD-L1 IC classification (JT test = 211, p < .001) and TIL score (r = 0.77). Cytokine therapy was associated with higher PD-L1 IC classification in 9/13 tumors, and increased PD-L1 ICs by mIHC in 14/15 (+337%, 95% CI: 120,769%). After adjusting for heterogeneity, cytokine therapy increased CD3+CD8+ ICs (+173%, CI: 93,287%) and CD3+CD8- ICs (+120%, CI: 21,301%). Therapy was also associated with increased effector-helper T-cell clustering (nearest-neighbor distance, -40%, CI: -29,-50%) and effector cell tumor localization (stromal-tumor interface CD8+ density +90%, Cl: 74, 305%). Conclusions: Our method is concordant with clinical PD-L1 and sTILs scores, and can additionally quantify IC and IC distances. This assay may allow for comparative I-O assessments with increased resolution, and will be used in a randomized phase II trial of pembrolizumab, chemo +/- IRX-2 in stage II/III TNBC.

scholarly journals Heterogeneity of Circulating Tumor Cell Neoplastic Subpopulations Outlined by Single-Cell Transcriptomics

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4885
Author(s):  
Christine M. Pauken ◽  
Shelby Ray Kenney ◽  
Kathryn J. Brayer ◽  
Yan Guo ◽  
Ursa A. Brown-Glaberman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Immune Cell ◽  
Metastatic Breast ◽  
Gene Expression Signature ◽  
Circulating Tumor Cell ◽  
Therapeutic Interventions ◽  
Cell Populations ◽  
Breast Cancer Patients ◽  
The Common

Fatal metastasis occurs when circulating tumor cells (CTCs) disperse through the blood to initiate a new tumor at specific sites distant from the primary tumor. CTCs have been classically defined as nucleated cells positive for epithelial cell adhesion molecule and select cytokeratins (EpCAM/CK/DAPI), while negative for the common lymphocyte marker CD45. The enumeration of CTCs allows an estimation of the overall metastatic burden in breast cancer patients, but challenges regarding CTC heterogeneity and metastatic propensities persist, and their decryption could improve therapies. CTCs from metastatic breast cancer (mBC) patients were captured using the RareCyteTM Cytefinder II platform. The Lin− and Lin+ (CD45+) cell populations isolated from the blood of three of these mBC patients were analyzed by single-cell transcriptomic methods, which identified a variety of immune cell populations and a cluster of cells with a distinct gene expression signature, which includes both cells expressing EpCAM/CK (“classic” CTCs) and cells possessing an array of genes not previously associated with CTCs. This study put forward notions that the identification of these genes and their interactions will promote novel areas of analysis by dissecting properties underlying CTC survival, proliferation, and interaction with circulatory immune cells. It improves upon capabilities to measure and interfere with CTCs for impactful therapeutic interventions.

scholarly journals Single-cell transcriptomics reveal the heterogeneity and dynamic of cancer stem-like cells during breast tumor progression

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Guojuan Jiang ◽  
Juchuanli Tu ◽  
Lei Zhou ◽  
Mengxue Dong ◽  
Jue Fan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Tumor Progression ◽  
Single Cell ◽  
Immune Cells ◽  
Breast Tumor ◽  
Immune Cell ◽  
Cell Lineage ◽  
Breast Tumor Progression

AbstractBreast cancer stem-like cells (BCSCs) play vital roles in tumorigenesis and progression. However, the origin and dynamic changes of BCSCs are still to be elucidated. Using the breast cancer mouse model MMTV-PyMT, we constructed a single-cell atlas of 31,778 cells from four distinct stages of tumor progression (hyperplasia, adenoma/MIN, early carcinoma and late carcinoma), during which malignant transition occurs. We identified that the precise cell type of ERlow epithelial cell lineage gave rise to the tumors, and the differentiation of ERhigh epithelial cell lineage was blocked. Furthermore, we discovered a specific signature with a continuum of gene expression profiles along the tumor progression and significantly correlated with clinical outcomes, and we also found a stem-like cell cluster existed among ERlow epithelial cells. Further clustering on this stem-like cluster showed several sub-clusters indicating heterogeneity of stem-like epithelial cells. Moreover, we distinguished normal and cancer stem-like cells in this stem-like epithelial cell cluster and profiled the molecular portraits from normal stem-like cell to cancer stem-like cells during the malignant transition. Finally, we found the diverse immune cell infiltration displayed immunosuppressive characteristics along tumor progression. We also found the specific expression pattern of cytokines and their corresponding cytokine receptors in BCSCs and immune cells, suggesting the possible cross-talk between BCSCs and the immune cells. These data provide a useful resource for illuminating BCSC heterogeneity and the immune cell remodeling during breast tumor progression, and shed new light on transcriptomic dynamics during the progression at the single-cell level.

scholarly journals COVID-19 Lung Pathogenesis in SARS-CoV-2 Autopsy Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvana Valdebenito ◽  
Simon Bessis ◽  
Djillali Annane ◽  
Geoffroy Lorin de la Grandmaison ◽  
Elisabeth Cramer–Bordé ◽  
...  
Keyword(s):  
Immune Response ◽  
Cellular Response ◽  
Immune Cell ◽  
Systemic Disease ◽  
Lung Damage ◽  
Public Health Issue ◽  
Alveolar Wall ◽  
Lung Pathology ◽  
Strong Immune Response ◽  
Immune Infiltration

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.

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