Immune gene signatures in triple-negative breast cancers characterized by varying levels of chromosomal instability.

1096 Background: Triple-negative breast cancer (TNBC) is generally characterized by high levels of chromosomal instability (CIN) and an intense immune infiltration. However, the link between these two hallmarks and its implications for clinical practice has not been fully elucidated. Methods: We generated eight immune metagenes representing various immune components: natural killer [NK], dendritic cells [DC], T-cells [TC], B-cells [BC], cytotoxic T-cells [CT], interferon [IFN], nuclear factor-κB [NF-kB], and macrophages [M]. Publicly available gene expression data from forty-two data sets, including 862 TNBC samples, were collected. TNBC tumors were clustered in three main subgroups (Basal-Like [BL1/2], Immunomodulatory [IM], and Mesenchymal/Mesenchymal Stem-Like [MS]) using transcriptomic profiling. The CIN70 signature was used to stratify TNBC patients according to the levels of CIN. Statistical analyses were performed using Mann–Whitney U test and Kaplan-Meier analyses. Results: The majority of TNBC samples showed a high level of CIN (83%), and several immune modules were differentially expressed between CIN-high and CIN-low tumors. Specifically, CT, NK, DC, M, and NF-kB signatures were overexpressed in CIN-low TNBC ( p < 1.0E-04). We then evaluated the distribution of genomic instability among TNBC molecular subgroups. Noteworthy, the CIN-high group was composed by a comparable proportion of BL1/2 (39%) and MS (35%) tumors, while CIN-low TNBCs were consistently enriched for MS cancers (61%). Higher expression of the NK, M, and IFN metagenes lead to better survival in CIN-high tumors ( p = 1.9E-02, p = 2.1E-04, and p = 1.1E-03, respectively). Only IFN had the same correlation to survival in CIN-low ( p = 1.4E-02). Conclusions: TNBCs with low levels of CIN may principally enclose M/MSL tumors, which are characterized by an intense immune infiltration and overall good prognosis. Conversely, the TNBC CIN-high group is more heterogeneous in terms of both biological features and levels of immune infiltrates. Therapeutic strategies to promote and boost immune response in the genomically unstable TNBC subgroup warrant further investigation.

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Infiltration of CD8+ T cells into tumor-cell clusters in Triple Negative Breast Cancer

10.1101/430413 ◽

2018 ◽

Author(s):

Xuefei Li ◽

Tina Gruosso ◽

Dongmei Zuo ◽

Atilla Omeroglu ◽

Sarkis Meterissian ◽

...

Keyword(s):

Mathematical Modeling ◽

T Cells ◽

T Lymphocytes ◽

Tumor Cell ◽

Triple Negative ◽

Good Prognosis ◽

Breast Cancers ◽

Spatial Profile ◽

Cell Clusters ◽

Modeling Analysis

Infiltration of CD8+ T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including Triple Negative Breast Cancers (TNBC). However, the mechanisms underlying different infiltration-levels are largely unknown. Here, we have characterized the spatial profile of CD8+ T cells around tumorcell clusters in the core and margin regions in TNBC. Combining mathematical modeling and data analysis, we propose that there exists a possible chemo-repellent inside tumor-cell clusters, which prevents CD8+ T cells from infiltrating into tumor-cell clusters. Furthermore, investigation into the properties of collagen fibers suggests that variations in desmoplastic elements does not limit infiltration of CD8+ T lymphocytes into tumor-cell clusters. This is consistent with the prediction of our mathematical modeling analysis whereby CD8+ T cells are predicted to infiltrate the fibrotic barrier and their infiltration into tumor clusters is governed by other mechanisms involving a local repellent.

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Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

Clinical & Translational Oncology ◽

10.1007/s12094-021-02652-3 ◽

2021 ◽

Author(s):

H. Kuroda ◽

T. Jamiyan ◽

R. Yamaguchi ◽

A. Kakumoto ◽

A. Abe ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Associated Macrophages ◽

Free Survival ◽

Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

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Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer

Cancers ◽

10.3390/cancers12113238 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3238

Author(s):

Mercedes Herrera ◽

Artur Mezheyeuski ◽

Lisa Villabona ◽

Sara Corvigno ◽

Carina Strell ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Immune Cell ◽

Therapeutic Potential ◽

Immune Surveillance ◽

Prognostic Significance ◽

Experimental Studies ◽

Population Based ◽

Good Prognosis ◽

High Group

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

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Phase I trial of advanced generation anti-CEA designer T cells in gastrointestinal and breast cancers

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15123 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15123-e15123

Author(s):

R. P. Junghans ◽

M. Abedi ◽

A. Bais ◽

E. Gomes ◽

Q. Ma ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Ex Vivo ◽

Cytotoxic T Cells ◽

Breast Cancers ◽

Cell Dose

e15123 Background: We created “designer T cells” by retroviral gene therapy to express chimeric immunoglobulin-T cell receptors (IgTCR) with specificity for carcinoembryonic antigen (CEA). Our previous Phase I trial with 1st generation (1st gen) designer T cells was well tolerated with proof-of-principle “biologic responses”, but of limited duration. Lab correlates showed modified T cells repeatedly kill tumor targets over 4–7 days but then undergo activation-induced cell death (AICD). We created 2nd gen designer T cells that incorporate CD28 co-stimulation into the IgTCR (IgCD28TCR), suppressing AICD and promoting T cell proliferation on tumor contact with superior tumor responses in vivo (Emtage et al. Clin Cancer Res 2008;14:8112). A Phase I clinical trial was approved under FDA BB-IND 10791. Methods: Patient T cells are modified ex vivo, expanded and then administered in a Phase Ia dose escalation, spanning doses of 10^9 to 10^11 cells. Patients are monitored for safety, pharmacokinetics and response. Results: To date, three subjects enrolled with doses prepared and two were treated. T cells were transduced with equal modification of CD4 helper and CD8 cytotoxic T cells and good ex vivo expansions of 30-fold or more. Cells were infused over 15–30 minutes. Blood clearance was rapid. Dosing was without toxicity but also without responses at this lowest T cell dose level. Results will be updated to include new patients at conference time. Conclusions: The safety of 2nd generation designer T cells is supported in two patients at the lowest T cell dose level. Higher planned doses are 10- to 100-fold more T cells, to be observed for toxicity and where responses may begin to be observed. Funding is from the Office of Orphan Products Development of the FDA. No significant financial relationships to disclose.

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Correlation of immune infiltration of cytotoxic T cells and activated microglia in glioblastoma (GBM) post anti-PD1 therapy with response.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.2055 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 2055-2055

Author(s):

Andrew Silverman ◽

Robyn Denise Gartrell ◽

Junfei Zhao ◽

Syeda Sabeeka Batool ◽

Thomas D Hart ◽

...

Keyword(s):

T Cells ◽

Cytotoxic T Cells ◽

Immune Infiltration ◽

Activated Microglia

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Abstract P1-07-14: Rates of immune infiltration in patients with triple-negative breast cancers by molecular subtype and in patients with inflammatory and non-inflammatory breast cancers

10.1158/1538-7445.sabcs16-p1-07-14 ◽

2017 ◽

Author(s):

K Harano ◽

Y Wang ◽

B Lim ◽

RS Seitz ◽

SW Morris ◽

...

Keyword(s):

Triple Negative ◽

Molecular Subtype ◽

Breast Cancers ◽

Immune Infiltration

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Immune-related biomarkers in triple-negative breast cancer

Breast Cancer ◽

10.1007/s12282-021-01247-8 ◽

2021 ◽

Author(s):

Juan Zhang ◽

Qi Tian ◽

Mi Zhang ◽

Hui Wang ◽

Lei Wu ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Combined Treatment ◽

Tumor Infiltrating Lymphocytes ◽

Molecular Characteristics ◽

Immune Gene ◽

Breast Cancers ◽

Related Factors ◽

Molecular Features

AbstractBreast cancer is a commonly diagnosed female cancer in the world. Triple-negative breast cancer (TNBC) is the most dangerous and biologically aggressive subtype in breast cancer which has a high mortality, high rates of relapse and poor prognosis, representing approximately 15–20% of breast cancers. TNBC has unique and special biological molecular characteristics and higher immunogenicity than other breast cancer types. On the basis of molecular features, TNBC is divided into different subtypes and gets various treatments. Especially, immunotherapy becomes a promising and effective treatment to TNBC. However, not all of the TNBC patients are sensitive to immunotherapy, the need of selecting the patients suitable for immunotherapy is imperative. In this review, we discussed recent discoveries about the immune-related factors of TNBC, including tumor-infiltrating lymphocytes (TILs), programmed death-ligand protein-1 (PD-L1), immune gene signatures, some other emerging biomarkers for immunotherapy effectivity and promising biomarkers for immunotherapy resistance. In addition, we summarized the features of these biomarkers contributing to predict the prognosis and effect of immunotherapy. We hope we can provide some helps or evidences to clinical immunotherapy and combined treatment for TNBC patients.

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CXCR2 Levels Correlate with Immune Infiltration and a Better Prognosis of Triple-Negative Breast Cancers

Cancers ◽

10.3390/cancers13102328 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2328

Author(s):

Florence Boissière-Michot ◽

William Jacot ◽

Océane Massol ◽

Caroline Mollevi ◽

Gwendal Lazennec

Keyword(s):

Cancer Progression ◽

Stromal Cells ◽

Triple Negative ◽

Univariate Analysis ◽

Tumor Infiltrating Lymphocytes ◽

Cytotoxic Lymphocytes ◽

Breast Cancers ◽

Immune Infiltration ◽

Chemokine Receptor Cxcr2 ◽

Low Levels

Chemokines and their receptors are key players in breast cancer progression and outcome. Previous studies have shown that the chemokine receptor CXCR2 was expressed at higher levels by cells of the tumor microenvironment in triple-negative breast cancers (TNBCs). The aim of this study was to focus our attention on a retrospective cohort of 290 TNBC cases and analyze the involvement of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) and their link with immune infiltration and immune checkpoint markers. We report that high densities of CXCR2-, CD11b- and CD66b-positive cells were associated with high-grade tumors. Moreover, molecular apocrine TNBCs, defined here as tumors that express both AR and FOXA1 biomarkers, exhibited low levels of CXCR2 and CD11b. High CXCR2 and CD11b levels were correlated with elevated density of tumor-infiltrating lymphocytes (TILs), CD8+ cytotoxic lymphocytes, expression of PD-L1 by tumor and stromal cells and of PD-1 by stromal cells. On the other hand, CD66b levels were associated only with CD8+, stromal PD-L1 and PD-1 expression. In univariate analysis, low levels of CXCR2 were correlated with poor OS and RFS. In multivariate analysis, low levels of CXCR2 were associated with poor OS. Finally, in TNBC treated with adjuvant chemotherapy, CXCR2 density was associated with longer RFS. Overall, our data highlight the potential beneficial association of high levels of CXCR2 with a subgroup of TNBC patients characterized by a better prognosis.

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