Associations of immune cell homing gene signatures and infiltrates of lymphocyte subsets in human melanomas: discordance with CD163+ myeloid cell infiltrates

Abstract Background Immune cells in the tumor microenvironment have prognostic value. In preclinical models, recruitment and infiltration of these cells depends on immune cell homing (ICH) genes such as chemokines, cell adhesion molecules, and integrins. We hypothesized ICH ligands CXCL9-11 and CCL2-5 would be associated with intratumoral T-cells, while CXCL13 would be more associated with B-cell infiltrates. Methods Samples of human melanoma were submitted for gene expression analysis and immune cells identified by immunohistochemistry. Associations between the two were evaluated with unsupervised hierarchical clustering using correlation matrices from Spearman rank tests. Univariate analysis performed Mann–Whitney tests. Results For 119 melanoma specimens, analysis of 78 ICH genes revealed association among genes with nonspecific increase of multiple immune cell subsets: CD45+, CD8+ and CD4+ T-cells, CD20+ B-cells, CD138+ plasma cells, and CD56+ NK-cells. ICH genes most associated with these infiltrates included ITGB2, ITGAL, CCL19, CXCL13, plus receptor/ligand pairs CXCL9 and CXCL10 with CXCR3; CCL4 and CCL5 with CCR5. This top ICH gene expression signature was also associated with genes representing immune-activation and effector function. In contrast, CD163+ M2-macrophages was weakly associated with a different ICH gene signature. Conclusion These data do not support our hypothesis that each immune cell subset is uniquely associated with specific ICH genes. Instead, a larger set of ICH genes identifies melanomas with concordant infiltration of B-cell and T-cell lineages, while CD163+ M2-macrophage infiltration suggesting alternate mechanisms for their recruitment. Future studies should explore the extent ICH gene signature contributes to tertiary lymphoid structures or cross-talk between homing pathways.

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Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression

Cell Discovery ◽

10.1038/s41421-020-00214-5 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Guohe Song ◽

Yang Shi ◽

Meiying Zhang ◽

Shyamal Goswami ◽

Saifullah Afridi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

T Cell ◽

Single Cell ◽

Immune Cells ◽

Immune Cell ◽

T Cell Subsets ◽

M2 Macrophage ◽

Advanced Hcc ◽

Immune Cell Subsets

AbstractDiverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.

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T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk

10.1101/2020.07.22.216564 ◽

2020 ◽

Author(s):

Dimitre R. Simeonov ◽

Harikesh S. Wong ◽

Jessica T. Cortez ◽

Arabella Young ◽

Zhongmei Li ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Regulatory T Cells ◽

Disease Progression ◽

Genetic Variants ◽

Immune Cell ◽

Disease Risk ◽

Autoimmune Diabetes ◽

Cell Subset ◽

Regulatory Elements

The majority of genetic variants associated with complex human autoimmune diseases reside in enhancers1–3, non-coding regulatory elements that control gene expression. In contrast with variants that directly alter protein-coding sequences, enhancer variants are predicted to tune gene expression modestly and function in specific cellular contexts4, suggesting that small alterations in the functions of key immune cell populations are sufficient to shape disease risk. Here we tested this concept by experimentally perturbing distinct enhancers governing the high affinity IL-2 receptor alpha chain (IL2RA; also known as CD25). IL2RA is an immune regulator that promotes the pro- and anti-inflammatory functions of conventional T cells (Tconvs) and regulatory T cells (Tregs), respectively, and non-coding genetic variants in IL2RA have been linked to multiple autoimmune disorders4. We previously tiled across the IL2RA locus using CRISPR-activation and identified a stimulation-responsive element (CaRE4) with an enhancer that modestly affects the kinetics of IL2RA expression in Tconvs5. This enhancer is conserved across species and harbors a common human SNP associated with protection from Type 1 Diabetes (T1D)5,6. We now identified an additional conserved enhancer, termed CaRE3 enhancer, which modestly affected steady state IL2RA expression in regulatory T cells (Tregs). Despite their seemingly subtle impact on gene expression, the CaRE3 and CaRE4 enhancers had pronounced yet divergent effects on the incidence of diabetes in autoimmune prone animals. Deletion of the conserved CaRE4 enhancer completely protected against autoimmune diabetes even in animals treated with an immunostimulating anti-PD1 checkpoint inhibitor, whereas deletion of the CaRE3 enhancer accelerated spontaneous disease progression. Quantitative multiplexed imaging of the pancreatic lymph nodes (panLNs) revealed that each enhancer deletion preferentially affected the protein expression levels of IL2RA in activated Tconvs or Tregs, reciprocally tuning local competition for IL-2 input signals. In animals lacking the CaRE4 enhancer, skewed IL-2 signaling favored Tregs, increasing their local density around activated Tconvs to strongly suppress emergence of autoimmune effectors. By contrast, in animals lacking the CaRE3 enhancer, IL-2 signals were skewed towards activated Tconvs, promoting their escape from Treg control. Collectively, this work illustrates how subtle changes in gene regulation due to non-coding variation can significantly alter disease progression and how distinct enhancers controlling the same gene can have opposing effects on disease outcomes through cell type-selective activity.

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DOP29 Elevation of a novel blood-based gene signature in a severe Crohn’s disease (CD) subtype preceding surgery defines and predicts a post-surgical decrease in pro-inflammatory pathway activation

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.068 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S068-S069

Author(s):

R Gonsky ◽

P Fleshner ◽

G Botwin ◽

E Biener-Ramanujan ◽

D McGovern ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

Cell Subset ◽

Gene Signature ◽

T Cell Subsets ◽

T Cell Subset ◽

Post Surgery ◽

Cell Gene Expression ◽

Cell Gene

Abstract Background CD is defined by transmural inflammation leading to inflammatory, stricturing and/or penetrating phenotypes. Identifying underlying molecular pathways and distinct disease subsets is critical for improved prognostics, therapeutics and biomarker discovery. Methods CD3+ T cells were purified from paired blood and mucosal tissue from 101 CD and 17 non-IBD subjects requiring surgery. Longitudinal samples (n = 30) were collected 4–13 mo. post-surgery. Expression profiles were generated by RNAseq, T-cell subset deconvolution by xCell and transcriptome-wide associations (TWAS) using TWAS-hub. Results Unsupervised clustering of peripheral T-cell gene expression at surgery revealed 2 CD profiles: Expression from cluster1, labelled CD-PBT (63%), clustered tightly with the non-IBD group. In cluster2, expression shifted from a peripheral toward a mucosal profile, labelled CD-PBmu(cosal) (37%). CD-PBmu was defined by differentially expressed genes (DEG) (1944 DEG, p < 0.001) regulating cell migration and adhesion pathways and a distinct T-cell subset composition associated with stricturing disease (p = 0.03), increased resected bowel length (p = 0.036) and post-op recurrence (p = 0.01). There were no significant differences in disease location/behaviour. Independent validation (5 public datasets) confirmed the CD-PBmu signature in data from whole blood (CD patients failing anti-TNF therapy, n = 204) and the mucosal-like expression profile in data from ileal tissue (paediatric CD patients, studies n = 751). A defining feature of CD-PBmu, validated in a separate CD cohort (n = 19), was decreased pro-inflammatory cytokine/chemokine and adhesion molecule expression following surgery (900 DEG, p < 0.001). No post-surgery change in expression was detected in CD-PBT. A 44-gene classifier was identified to enable clinical application. The classifier accurately detected the CD-PBmu patient subtype, correlated with the altered composition of peripheral T-cell subsets and overlapped with IBD associated TWAS signals (>60%). Recently, another group posed a blood-based 17 gene panel as predictive for aggressive IBD. These genes were not predictive for either the CD-PBmu or CD-PBT subtype (<50% DEG). Conclusion Severe CD can be stratified into 2 subtypes based on peripheral T-cell gene expression. Circulating T cells from CD-PBmu exhibit a mucosal-like gene signature, altered T-cell subset composition, clinical features of severity and decreased pro-inflammatory gene expression post-surgery. These findings hold potential to identify targets for CD subtype-specific therapeutic development. The 44-gene classifier overlapped with multiple paediatric CD datasets, suggesting the potential application of these findings for treatment stratification early in the disease process.

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Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001125 ◽

2021 ◽

Vol 9 (2) ◽

pp. e1125

Author(s):

Rui Li ◽

Thomas Francis Tropea ◽

Laura Rosa Baratta ◽

Leah Zuroff ◽

Maria E. Diaz-Ortiz ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Parkinson Disease ◽

B Cell ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Ex Vivo ◽

Cell Counts

Background and ObjectivesThere has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls.MethodsPeripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses.ResultsThe discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality.DiscussionOur findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

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Impact of Tumor Infiltrating T Cells in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1572.1572 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1572-1572

Author(s):

Shahryar Kiaii ◽

Andrew James Clear ◽

John G Gribben

Keyword(s):

Gene Expression ◽

T Cells ◽

B Cell ◽

Immune Cells ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Treated Group ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 1572 Previous studies have demonstrated the importance of the non-malignant tumor-infiltrating immune cells in the tumor microenvironment at diagnosis in patients with non-Hodgkin's lymphoma (NHL). We aimed to investigate the molecular mechanisms whereby tumor infiltrating T cells (TILs) are altered in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We used gene expression profiling of highly purified CD4 and CD8 infiltrating T-cells (TILs) from FL patients and reported that PMCH, ETV1 and NAMPT are highly expressed in both CD4 and CD8 TILs and showed in tissue microarrays (TMA) that expression of pro-melanin-concentrating hormone (PMCH), ets variant 1 (ETV1) and nicotinamide phosphoribosyltransferase (NAMPT) in T-cells have prognostic impact in disease specific survivals (DSS) and time to transformation (TT) in patients with FL. In addition, PMCH and NAMPT were shown to be independently significant in TT in multivariate analysis. We next examined expression of these gene products in T cells in FL samples before and after transformation to DLBCL (n=29). Comparing total number of positive cells for expression of proteins of interest, we demonstrate there is a significant decline in PMCH (p=0.035), EVT1 (p=0.018) and NAMPT (p=0.0136) expressing cells after transformation. We further investigated the prognostic impact of expression of these proteins in T cells in patients with DLBCL in two treatment groups, those receiving rituximab (n=68) and in a historic non-rituximab (n=130) treated cohort. By assessing the number of positive cells and the impact on survival using Kaplan-Meier analysis, we now show that the T-cell expressed genes PMCH, ETV1 and NAMPT have prognostic significance for overall survival (OS) in patients with DLBCL. Patients with higher number of PMCH expressing T-cells showed significant longer survivals in both rituximab (p=0.027) and non-rituximab (p=0.033) treated groups. In contrast to PMCH, and in line with our previous data in FL, patients with higher number of NAMPT expressing cells showed significantly shorter OS in the rituximab (p=0.046) treated group, with a trend towards shorter OS in non-rituximab (p=0.064) treated group. Patients with higher percentage of ETV1 expressing cells had longer OS in the non-Rituximab group (p=0.008), with only a trend towards OS with rituximab treatment (p=0.067). We are examining this further in a larger cohort of rituximab treated patients. Our previous data has indicated that TILs in patients with FL are abnormal in terms of their gene expression and function. We now show that changes in protein expression in TILs have an impact on transformation in patients with FL and on survival in both FL and DLBCL. We are further characterizing the mechanisms of gene expression alteration in TILs of patients with FL and DLBCL and its functional consequences in the biology and of the disease. It appears that altered gene expression in TILs plays a fundamental role in transformation and may be important in the survivals and biology of NHL. Since non-malignant infiltrating immune cells have a crucial role in the outcome of patients with FL and DLBCL, understanding the nature and impact of the abnormalities induced in TILs in these patients is crucial before any immunotherapeutic strategies can be implemented to attempt to alter the immune microenvironment in NHL. Disclosures: Gribben: Celgene: Honoraria.

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Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00075.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. E528-E539 ◽

Cited By ~ 2

Author(s):

Katya B. Rubinow ◽

Jing H. Chao ◽

Derek Hagman ◽

Mario Kratz ◽

Brian Van Yserloo ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Adipose Tissue ◽

Immune Cells ◽

Immune Cell ◽

Sex Steroid ◽

Cell Populations ◽

Male Hypogonadism ◽

Healthy Men ◽

Testosterone Gel

Male hypogonadism results in changes in body composition characterized by increases in fat mass. Resident immune cells influence energy metabolism in adipose tissue and could promote increased adiposity through paracrine effects. We hypothesized that manipulation of circulating sex steroid levels in healthy men would alter adipose tissue immune cell populations. Subjects ( n = 44 men, 19–55 yr of age) received 4 wk of treatment with the gonadotropin-releasing hormone receptor antagonist acyline with daily administration of 1) placebo gel, 2) 1.25 g testosterone gel (1.62%), 3) 5 g testosterone gel, or 4) 5 g testosterone gel with an aromatase inhibitor. Subcutaneous adipose tissue biopsies were performed at baseline and end-of-treatment, and adipose tissue immune cells, gene expression, and intra-adipose estrogen levels were quantified. Change in serum total testosterone level correlated inversely with change in the number of CD3+ (β = −0.36, P = 0.04), CD4+ (β = −0.34, P = 0.04), and CD8+ (β = −0.33, P = 0.05) T cells within adipose tissue. Change in serum 17β-estradiol level correlated inversely with change in the number of adipose tissue macrophages (ATMs) (β = −0.34, P = 0.05). A negative association also was found between change in serum testosterone and change in CD11c+ ATMs (β = −0.41, P = 0.01). Overall, sex steroid deprivation was associated with increases in adipose tissue T cells and ATMs. No associations were found between changes in serum sex steroid levels and changes in adipose tissue gene expression. Circulating sex steroid levels may regulate adipose tissue immune cell populations. These exploratory findings highlight a possible novel mechanism that could contribute to increased metabolic risk in hypogonadal men.

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A gene expression-based study on immune cell subtypes and glioma prognosis

BMC Cancer ◽

10.1186/s12885-019-6324-7 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 5

Author(s):

Qiu-Yue Zhong ◽

Er-Xi Fan ◽

Guang-Yong Feng ◽

Qi-Ying Chen ◽

Xiao-Xia Gou ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Data Analysis ◽

Nk Cells ◽

Immune Cells ◽

Prognostic Value ◽

Immune Cell ◽

High Morbidity ◽

Gamma Delta T Cells ◽

Gamma Delta

Abstract Object Glioma is a common malignant tumours in the central nervous system (CNS), that exhibits high morbidity, a low cure rate, and a high recurrence rate. Currently, immune cells are increasingly known to play roles in the suppression of tumourigenesis, progression and tumour growth in many tumours. Therefore, given this increasing evidence, we explored the levels of some immune cell genes for predicting the prognosis of patients with glioma. Methods We extracted glioma data from The Cancer Genome Atlas (TCGA). Using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm, the relative proportions of 22 types of infiltrating immune cells were determined. In addition, the relationships between the scales of some immune cells and sex/age were also calculated by a series of analyses. A P-value was derived for the deconvolution of each sample, providing credibility for the data analysis (P < 0.05). All analyses were conducted using R version 3.5.2. Five-year overall survival (OS) also showed the effectiveness and prognostic value of each proportion of immune cells in glioma; a bar plot, correlation-based heatmap (corheatmap), and heatmap were used to represent the proportions of immune cells in each glioma sample. Results In total, 703 transcriptomes from a clinical dataset of glioma patients were drawn from the TCGA database. The relative proportions of 22 types of infiltrating immune cells are presented in a bar plot and heatmap. In addition, we identified the levels of immune cells related to prognosis in patients with glioma. Activated dendritic cells (DCs), eosinophils, activated mast cells, monocytes and activated natural killer (NK) cells were positively related to prognosis in the patients with glioma; however, resting NK cells, CD8+ T cells, T follicular helper cells, gamma delta T cells and M0 macrophages were negatively related to prognosis in the patients with glioma. Specifically, the proportions of several immune cells were significantly related to patient age and sex. Furthermore, the level of M0 macrophages was significant in regard to interactions with other immune cells, including monocytes and gamma delta T cells, in glioma tissues through sample data analysis. Conclusion We performed a novel gene expression-based study of the levels of immune cell subtypes and prognosis in glioma, which has potential clinical prognostic value for patients with glioma.

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Research progress on the role of immune cells in Brucella infection

Infection International ◽

10.2478/ii-2018-0014 ◽

2018 ◽

Vol 7 (1) ◽

pp. 23-27 ◽

Cited By ~ 3

Author(s):

Jin Zhang

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cells ◽

Immune Cell ◽

Cell Subset ◽

Animal Husbandry ◽

Research Progress ◽

Human Beings ◽

T Cell Subset ◽

Th2 Cell

Abstract Brucellosis is one of the most prevalent zoonoses in the world. Incidence of the disease has increased significantly in recent years and has seriously affected the health of human beings and the development of animal husbandry. The pathogenesis of brucellosis remains unclear. Current studies suggest that this disease may be related to changes in natural killer cells, dendritic cells, and macrophages in immune cell subsets. Brucellosis may be also related to T helper (Th) 1 cell/Th2 cell imbalance in the CD4+ T cell subset, immunoregulation of regulatory T cells and Th17 cells, and the mechanism of action of CD8+ T cell. This paper aims to review the research progress on these inherent immune cells, the CD4+ T cell subset, and CD8+ T cells in Brucella infection.

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The Immune Cell Landscape in Renal Allografts

Cell Transplantation ◽

10.1177/0963689721995458 ◽

2021 ◽

Vol 30 ◽

pp. 096368972199545

Author(s):

Jun Lu ◽

Yi Zhang ◽

Jingjing Sun ◽

Shulin Huang ◽

Weizhen Wu ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

Immune Cells ◽

Immune Cell ◽

Cell Infiltration ◽

M1 Macrophages ◽

Deconvolution Analysis ◽

Renal Allografts ◽

Antibody Mediated Rejection

Immune cell infiltration plays an important role in the pathophysiology of kidney grafts, but the composition of immune cells is ill-defined. Here, we aimed at evaluating the levels and composition of infiltrating immune cells in kidney grafts. We used CIBERSORT, an established algorithm, to estimate the proportions of 22 immune cell types based on gene expression profiles. We found that non-rejecting kidney grafts were characteristic with high rates of M2 macrophages and resting mast cells. The proportion of M1 macrophages and activated NK cells were increased in antibody-mediated rejection (ABMR). In T cell-mediated rejection (TCMR), a significant increase in CD8 T cell and γδT cell infiltration was observed. CD8 positive T cells were dramatically increased in mixed-ABMR/TCMR. Then, the function of ABMR and TCMR prognostic molecular biomarkers were identified. Finally, we described the gene expression of molecular markers for ABMR diagnosis was elevated and related to the ratio of monocytes and M1 macrophages in ABMR biopsies, while the expression of TCMR diagnosis markers was increased too and positively correlated with γδT cells and activated CD4 memory T cells in TCMR biopsies. Our data suggest that CIBERSORT’s deconvolution analysis of gene expression data provides valuable information on the composition of immune cells in renal allografts.

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Procancerous immune cells in primary tumor is associated with breast cancer recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13042 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13042-e13042

Author(s):

Takashi Takeshita ◽

Li Yan ◽

Kazuaki Takabe

Keyword(s):

Gene Expression ◽

T Cells ◽

Immune Cells ◽

Clinical Characteristics ◽

Immune Cell ◽

Cancer Recurrence ◽

Early Death ◽

Late Recurrence ◽

Gene Expression Signatures ◽

Or Gene

e13042 Background: Breast cancer (BC) recurrence is largely determined by cancer factors as well as host factors. It has been implicated that infiltrating immune cells play critical roles in long term survival. We hypothesize that immune cell infiltration profile rather than clinical characteristics or gene expression signatures of the primary tumors associate with the timing of cancer recurrence. Methods: 308 primary BCs in TCGA with cancer recurrence data was divided into; recurrence < 2 years (Early, n = 103), 2-5 years (Late, n = 20), and no recurrence > 5 years (Control, n = 185). 1410 primary BCs in METABRIC with BC specific death data was divided into; death < 10 years (Early Death, n = 499), death > 10 years (Late Death, n = 123), and survived > 10 years (Survivors, n = 788). Results: We found that Early tumors demonstrated more aggressive clinical characteristics such as larger tumor, more lymph node metastases, higher pathological grades, higher Stages, and negative estrogen and progesterone receptors, compared with Control tumors. On the other hand, no clinical characteristics of Late tumors were significantly different from Control tumors, which implicate that clinical characteristics cannot distinguish late recurrence from Control. Gene set enrichment analyses revealed that there was no significant gene sets that enriched with Early nor Late recurrence compared with Control, which implicate that gene expression signatures cannot distinguish recurrent tumor from Control. Utilizing CIBERSORT algorithm, we found that M1 was low and M2 was high macrophages in Early compared from Control. Further, anti-cancer lymphocytes, memory CD4 T cells and gamma delta T cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Early and Late compared from Control. In agreement, cytolytic activity score that assess immune cell killing were significantly lower in Early and Late compared from Control. Interestingly, only elevation of regulatory T cells was similar in METABRIC cohort when Early Death and Late Death were compared with Survivors. Conclusions: We found that not clinical characteristics or gene expression signatures, but pro-cancerous immune cells in primary BC associate with cancer recurrence and breast specific death.

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