Prognostic Impact of Cytotoxic CD4 T Cells in Tumor Immune Microenvironment of Patients with Breast Cancer

e12573 Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p < 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p < 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.

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RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.650499 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lan-Xin Mu ◽

You-Cheng Shao ◽

Lei Wei ◽

Fang-Fang Chen ◽

Jing-Wei Zhang

Keyword(s):

Breast Cancer ◽

Immune Cell ◽

Risk Model ◽

Cox Regression ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Impact ◽

Immune Microenvironment ◽

Model Based ◽

Tumor Immune Microenvironment

Purpose: This study aims to reveal the relationship between RNA N6-methyladenosine (m6A) regulators and tumor immune microenvironment (TME) in breast cancer, and to establish a risk model for predicting the occurrence and development of tumors.Patients and methods: In the present study, we respectively downloaded the transcriptome dataset of breast cancer from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database to analyze the mutation characteristics of m6A regulators and their expression profile in different clinicopathological groups. Then we used the weighted correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and cox regression to construct a risk prediction model based on m6A-associated hub genes. In addition, Immune infiltration analysis and gene set enrichment analysis (GSEA) was used to evaluate the immune cell context and the enriched gene sets among the subgroups.Results: Compared with adjacent normal tissue, differentially expressed 24 m6A regulators were identified in breast cancer. According to the expression features of m6A regulators above, we established two subgroups of breast cancer, which were also surprisingly distinguished by the feature of the immune microenvironment. The Model based on modification patterns of m6A regulators could predict the patient’s T stage and evaluate their prognosis. Besides, the low m6aRiskscore group presents an immune-activated phenotype as well as a lower tumor mutation load, and its 5-years survival rate was 90.5%, while that of the high m6ariskscore group was only 74.1%. Finally, the cohort confirmed that age (p < 0.001) and m6aRiskscore (p < 0.001) are both risk factors for breast cancer in the multivariate regression.Conclusion: The m6A regulators play an important role in the regulation of breast tumor immune microenvironment and is helpful to provide guidance for clinical immunotherapy.

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Association of Th2 high tumors with aggressive features of breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e12584 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e12584-e12584

Author(s):

Yoshihisa Tokumaru ◽

Lan Le ◽

Masanori Oshi ◽

Eriko Katsuta ◽

Nobuhisa Matsuhashi ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Progression ◽

Immune Cells ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Th2 Cells ◽

Immune Microenvironment ◽

Adaptive Immune Cells ◽

Tumor Immune Microenvironment

e12584 Background: Recent studies have shown that infiltrating T-lymphocytes have been implicated in the promotion of breast cancer progression. Upon activation, these antigen-presenting cells then recruit adaptive immune cells. It has been proposed that polarization of CD4+ effector T-cells towards the immunosuppressive Th2 cells induce cytokine release and T-cell anergy, which lead to polarization of M2 tumor-associated macrophages (TAM’s), providing a protumorigenic microenvironment. We hypothesized that there is a correlation between high levels of Th2 cells and aggressive features of breast cancer and unfavorable tumor immune environment. Methods: Clinicopathological data and overall survival information was obtained on 1069 breast cancer patients from The Cancer Genome Atlas (TCGA) database. We defined Th2 high and low levels with the median cutoff. Results: Analysis of cell composition of the immune cells within tumor immune microenvironment demonstrated that Th2 high tumors did not consistently associated with unfavorable tumor immune microenvironment. Pro-cancer immune cells, such as macrophage M2 cells were increased with Th2 high tumors whereas, regulatory T cells were decreased with Th2 high tumors (p < 0.01 and p < 0.001 respectively). On the contrary, infiltration of anti-cancer cells, such as macrophage M1 was increased whereas CD8 T cells were decreased with Th2 high tumors (p < 0.05 and p < 0.001 respectively). Th2 was not shown to have correlation with IL-4, IL-6, IL-10 and IL-13, all of which has been reported to associate with Th2 cells. Th2 levels were associated with advanced grades. Also, correlation analysis demonstrated that there was a strong correlation between Th2 levels and Ki-67. These results were further validated with gene set enrichment analysis (GSEA). GSEA revealed that in Th2 high tumors enriched the gene sets associated with cell proliferation and cell cycle. Conclusions: High expression of immunosuppressive Th2 cells was associated with highly proliferative features of breast cancer, but not with unfavorable tumor immune microenvironment.

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Screening of tumor microenvironment-related prognostic genes in breast cancer by data mining

10.21203/rs.2.24359/v1 ◽

2020 ◽

Author(s):

Yunhui LI ◽

Na REN

Keyword(s):

Breast Cancer ◽

T Cells ◽

B Cells ◽

Memory T Cells ◽

Immune Therapy ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Immune Score

Abstract Background Accumulating evidence has demonstrated that the components of tumor immune microenvironment (TME) play important roles in breast cancer (BC) initiation, progression and prognosis. Materials and methods We downloaded the TCGA, GSE12276, GSE58812 and GSE42568 datasets. We calculated the immune scores and tumor immune infiltrating cells (TIICs) of TCGA-BRCA and GEO datasets using ESTIMATE and CIBERSORT algorithm, respectively. Then, the overlapping immune-related differentially expressed genes (DEGs) were screened using R ‘limma ’ package between TCGA and GSE12276 datasets. The GO and KEGG enrichment analysis were used to predict the function and signaling pathways of common DEGs. Finally, we extracted a series of tumor immune microenvironment-related genes, and explore the relationship between these genes and clinical outcomes in TCGA, GSE58812 and GSE42568 datasets. Results Based on the ESTIMATE algorithm, the immune scores were significantly associated with cancer types, as well as overall survival in BC patients. The fractions of some TIICs, such asnaïve B cells, memory B cells, CD8 + T cells, resting CD4 + memory T cells, activated CD4 + memory T cells, resting NK cells, monocytes, macrophage M0, M1, M2, resting DCs, activated DCs and resting mast cells, were significantly different between low and high immune score groups (all P <0.05). The DEGs between low and high immune score groups were mainly involved in immune-related biological processes, including adaptive immune response, innate response and inflammatory response. Finally, we found that ACSL5, GIMAP2, HLA-DRA and CLEC10A were significantly associated with prognosis among TCGA, GASE58812 and GSE42568 datasets (all P <0.05). Conclusion These findings provide a more comprehensive understanding of immune cells and immune-related genes within TME as well as prognosis-related genes in BC. Future studies need to perform in vivo and in vitro experiments to clarify the mechanisms of these genes in TME and provide a comprehensive idea to immune therapy.

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Disparity in Tumor Immune Microenvironment of Breast Cancer and Prognostic Impact: Asian Versus Western Populations

The Oncologist ◽

10.1634/theoncologist.2019-0123 ◽

2019 ◽

Vol 25 (1) ◽

Cited By ~ 8

Author(s):

Ching‐Hsuan Chen ◽

Yen‐Shen Lu ◽

Ann‐Lii Cheng ◽

Chiun‐Sheng Huang ◽

Wen‐Hung Kuo ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Impact ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

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Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment

Cancers ◽

10.3390/cancers13112559 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2559

Author(s):

Shipra Gandhi ◽

Masanori Oshi ◽

Vijayashree Murthy ◽

Elizabeth A. Repasky ◽

Kazuaki Takabe

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cold Stress ◽

Triple Negative Breast Cancer ◽

Cancer Biology ◽

Triple Negative ◽

Related Gene ◽

Immune Microenvironment ◽

Gene Sets ◽

Tumor Immune Microenvironment

Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.

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Deciphering the nexus between the tumor immune microenvironment and DNA methylation in subgrouping estrogen receptor-positive breast cancer

Breast Cancer ◽

10.1007/s12282-021-01262-9 ◽

2021 ◽

Author(s):

Xiao-Qiong Chen ◽

Fan Zhang ◽

Fu-Hui Xiao ◽

Yu Peng

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Estrogen Receptor ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

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Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression

Blood Cancer Journal ◽

10.1038/s41408-021-00440-4 ◽

2021 ◽

Vol 11 (3) ◽

Author(s):

Alissa Visram ◽

Surendra Dasari ◽

Emilie Anderson ◽

Shaji Kumar ◽

Taxiarchis V. Kourelis

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Plasma Cells ◽

Malignant Cell ◽

Immune Microenvironment ◽

Cytokine Analysis ◽

Tumor Immune Microenvironment ◽

Early Memory ◽

E2f Transcription Factors ◽

Cluster 2

AbstractImmunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed [NDMM], 11 relapsed pre-daratumumab exposure [RMM], and 13 triple-refractory [TRMM]) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.

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