Depression, Anxiety, and Social Environmental Adversity as Potential Modulators of the Immune Tumor Microenvironment in Breast Cancer Patients

Background: Mounting data suggest that exposure to chronic stress is associated with worse breast cancer outcomes. This study aimed to explore the impact of social environmental adversity (SEA, e.g., child abuse, crime, sexual, and physical violence), depressive symptomatology, and anxiety on immune cell infiltration into the breast tumor microenvironment. Methods: Participants (n = 33) completed a series of surveys assessing depression and anxiety symptoms, adverse childhood events (ACE), and trauma history. Tumor-associated macrophages (CD68+), B cells (CD19+), and T cells (CD3+) were identified by immunohistochemical analyses of formalin-fixed paraffin-embedded tumor samples and quantified. Spearman rank tests were used to explore the relationships between the variables studied. Results: Exposure to SEA was high (ACE = 72%, exposure to crime = 47%, and exposure to physical/sexual assault = 73%) among participants. Moreover, 30% reported a comorbid history of depression and ACE; 39% reported one or more traumatic events, and clinically significant depression symptomatology, while 21% reported trauma history and significant anxiety symptomatology. Increased tumor-infiltrating B cells were significantly correlated with exposure to crime, anxiety symptoms, and exposure to an ACE. The ACE plus anxiety group presented the highest infiltration of B cells, T cells, and macrophages. Conclusion: These findings support a role for SEA, anxiety symptoms, and depression as potential modulators of the immune tumor microenvironment in breast cancer.

Download Full-text

Effect of TCHL-based therapy on immune cell content in on-treatment, neoadjuvant-treated HER2-positive breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.583 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 583-583

Author(s):

Niamh M. Keegan ◽

Sinead Toomey ◽

Joanna Fay ◽

Stephen F. Madden ◽

Bruce Moran ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Immune Cell ◽

Cell Populations ◽

Breast Cancer Patients ◽

Myeloid Dendritic Cells ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

The Impact ◽

Positive Breast Cancer

583 Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.

Download Full-text

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

Cancers ◽

10.3390/cancers13143450 ◽

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.

Download Full-text

Single-cell RNA-Seq reveals transcriptional heterogeneity and immune subtypes associated with disease activity in human myasthenia gravis

Cell Discovery ◽

10.1038/s41421-021-00314-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Wanlin Jin ◽

Qi Yang ◽

Yuyao Peng ◽

Chengkai Yan ◽

Yi Li ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Myasthenia Gravis ◽

Disease Activity ◽

Single Cell ◽

Immune Cell ◽

Large Cell ◽

Cellular Heterogeneity ◽

T Cell Subsets ◽

The Impact

AbstractMyasthenia gravis (MG) is a rare autoimmune disease. Although the impact of immune cell disorder in MG has been extensively studied, little is known about the transcriptomes of individual cells. Here, we assessed the transcriptional profiles of 39,243 cells by single-cell sequencing and identified 13 major cell clusters, along with 39 subgroups of cells derived from patients with new-onset myasthenia gravis and healthy controls. We found that B cells, CD4+ T cells, and monocytes exhibited more heterogeneity in MG patients. CD4+ T cells were expanded in MG patients. We reclustered B cells and CD4+ T cells, and predict their essential regulators. Further analyses demonstrated that B cells in MG exhibited higher transcriptional activity towards plasma cell differentiation, CD4+ T cell subsets were unbalanced, and inflammatory pathways of monocytes were highly activated. Notably, we discovered a disease-relevant subgroup, CD180− B cells. Increased CD180− B cells in MG are indicative of a high IgG composition and were associated with disease activity and the anti-AChR antibody. Together, our data further the understanding of the cellular heterogeneity involved in the pathogenesis of MG and provide large cell-type-specific markers for subsequent research.

Download Full-text

Fractal dimension, occupancy and hotspot analyses of B cell spatial distribution predict clinical outcome in breast cancer

10.1101/678607 ◽

2019 ◽

Author(s):

Juliana C. Wortman ◽

Ting-Fang He ◽

Shawn Solomon ◽

Robert Z. Zhang ◽

Anthony Rosario ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Spatial Distribution ◽

B Cells ◽

Clinical Outcome ◽

Immune Cells ◽

Triple Negative ◽

Immune Cell ◽

Statistical Techniques ◽

Killer T Cells

AbstractWhile the density of tumor-infiltrating lymphocytes (TILs) is now well known to correlate with clinical outcome, the clinical significance of spatial distribution of TILs is not well characterized. We have developed novel statistical techniques (including fractal dimension differences, a hotspot analysis, a box counting method that we call ‘occupancy’ and a way to normalize cell density that we call ‘thinning’) to analyze the spatial distribution (at different length scales) of various types of TILs in triple negative breast tumors. Consistent with prior reports, the density of CD20+ B cells within tumors is not correlated with clinical outcome. However, we found that their spatial distribution differs significantly between good clinical outcome (no recurrence within at least 5 years of diagnosis) and poor clinical outcome (recurrence with 3 years of diagnosis). Furthermore, CD20+ B cells are more spatially dispersed in good outcome tumors and are more likely to infiltrate into cancer cell islands. Lastly, we found significant correlation between the spatial distributions of CD20+ B cells and CD8+ (cytotoxic) T cells (as well as CD3+ T cells), regardless of outcome. These results highlight the significance of the spatial distribution of TILs, especially B cells, within tumors.Significance StatementImmune cells can fight cancer. For example, a patient has a good prognosis when a high density of killer T cells, a type of immune cell that can kill cancer cells, infiltrates into a tumor. However, there is no clear association between prognosis and the density of B cells, another type of immune cell, in a tumor. We developed several statistical techniques to go beyond cell density and look at the spatial distribution, i.e., the pattern or arrangement of immune cells, in tumors that have been removed from patients with triple negative breast cancer. We find that B cells and killer T cells tend to be more spread out in the tumors of patients whose cancer did not recur.

Download Full-text

Classification of triple-negative breast cancer based on immune cell infiltration

10.21203/rs.3.rs-43664/v1 ◽

2020 ◽

Author(s):

Wenji Shi ◽

Dan Wang ◽

Luz Angela Torres-de la Roche ◽

Rui Zhuo ◽

Rudy Leon De Wilde

Keyword(s):

Breast Cancer ◽

T Cells ◽

B Cells ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Immune Phenotype ◽

Cluster A

Abstract Background Although the classification system of triple-negative breast cancer(TNBC) has become more and more perfect, there is no report on the immune subtype of triple-negative breast cancer based on immune cell infiltration. Results According to immune infiltrating cells, data from 360 patients were divided into cluster A (subtype 1 and subtype 3) and cluster B (subtype 2; with poorly immune phenotype). Expression of memory B cells, naïve B cells, M0 macrophages, M1 macrophages, CD4 memory activated T cells, and CD4 naïve T cells were significantly higher in cluster A (P < 0.05). In contrast, the expression of M2 macrophages and resting mast cells were higher in cluster B (P < 0.05). GSVA results show that B cell receptor pathway and JAK-STAT pathway are activated and more frequently altered in cluster A (P < 0.05). mTOR pathway alterations usually appear in cluster B (P < 0.05). Compared with cluster A, the risk of recurrence in cluster B patients is significantly increased (P < 0.05). Conclusions This analysis of tumor microenvironment revealed the multifaceted nature of TNBC and its impact on patient prognosis, being recurrence more often in those with poorly immune phenotype. These results provide a reference for further exploration of the heterogeneity of TNBC.

Download Full-text

Longitudinal study of DNA methylation and epigenetic clocks prior to and following test-confirmed COVID-19 and mRNA vaccination

10.1101/2021.12.01.21266670 ◽

2021 ◽

Author(s):

Alina PS Pang ◽

Albert T. Higgins-Chen ◽

Florence Comite ◽

Ioana Raica ◽

Christopher Arboleda ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

B Cells ◽

Immune Cell ◽

Principal Component ◽

Epigenetic Clock ◽

Cell Type ◽

Immune Cell Type ◽

Compositional Changes ◽

The Impact

AbstractThe host epigenetic landscape is rapidly changed during SARS-CoV-2 infection and evidence suggests that severe COVID-19 is associated with durable scars to the epigenome. Specifically, aberrant DNA methylation changes in immune cells and alterations to epigenetic clocks in blood relate to severe COVID-19. However, a longitudinal assessment of DNA methylation states and epigenetic clocks in blood from healthy individuals prior to and following test-confirmed non-hospitalized COVID-19 has not been performed. Moreover, the impact of mRNA COVID-19 vaccines upon the host epigenome remains understudied. Here, we first examined DNA methylation states in blood of 21 participants prior to and following test confirmed COVID-19 diagnosis at a median timeframe of 8.35 weeks. 261 CpGs were identified as differentially methylated following COVID-19 diagnosis in blood at an FDR adjusted P value <0.05. These CpGs were enriched in gene body and northern and southern shelf regions of genes involved in metabolic pathways. Integrative analysis revealed overlap among genes identified in transcriptional SARS-CoV-2 infection datasets. Principal component-based epigenetic clock estimates of PhenoAge and GrimAge significantly increased in people over 50 following infection by an average of 2.1 and 0.84 years. In contrast, PCPhenoAge significantly decreased in people under 50 following infection by an average of 2.06 years. This observed divergence in epigenetic clocks following COVID-19 was related to age and immune cell-type compositional changes in CD4+ T cells, B cells, granulocytes, plasmablasts, exhausted T cells, and naïve T cells. Complementary longitudinal epigenetic clock analyses of 36 participants prior to and following Pfizer and Moderna mRNA-based COVID-19 vaccination revealed vaccination significantly reduced principal component-based Horvath epigenetic clock estimates in people over 50 by an average of 3.91 years for those that received Moderna. This reduction in epigenetic clock estimates was significantly related to chronological age and immune cell-type compositional changes in B cells and plasmablasts pre- and post-vaccination. These findings suggest the potential utility of epigenetic clocks as a biomarker of COVID-19 vaccine responses. Future research will need to unravel the significance and durability of short-term changes in epigenetic age related to COVID-19 exposure and mRNA vaccination.

Download Full-text

A Diet High in Lipid Soluble Forms of Choline Modulates Gut-Associated Immune Function in Sprague-Dawley Dams

Current Developments in Nutrition ◽

10.1093/cdn/nzab061_003 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1119-1119

Author(s):

Jessy Azarcoya Barrera ◽

Dhruvesh Patel ◽

Catherine Field ◽

Yves Pouliot ◽

Susan Goruk ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Immune Responses ◽

Oral Tolerance ◽

Immune Cell ◽

Ex Vivo ◽

Control Diet ◽

Sprague Dawley ◽

And Control ◽

The Impact

Abstract Objectives Oral tolerance is the state of unresponsiveness to dietary antigens that are not harmful to the host, a process that begins in the gut and influences both local and peripheral immune responses. Lipid soluble forms of choline have been shown to beneficial affect peripheral immune responses during pregnancy and lactation, yet little is known about the impact of the different choline forms on the gut-associate lymphoid tissue (GALT). Therefore, the objective of this study was to determine the effect of feeding buttermilk-derived choline forms on the GALT in lactating dams. Methods Sprague-Dawley dams were randomized to consume one of three diets, all containing 1.9 g/kg of total choline: 1-Control (100% free choline (FC)), 2-Buttermilk (37% phosphatidylcholine (PC), 34% sphingomyelin, 17% glycerophosphocholine (GPC), 7% FC, 5% phosphocholine) and 3-Placebo (50% PC, 25% FC, 25% GPC). Immune cell phenotypes of mesenteric lymph nodes (MLN) and Peyer's patches (PP) were measured by flow cytometry. Ex vivo cytokine production by immune cells isolated from MLN stimulated with Concanavalin A (ConA) and Ovalbumin (OVA) was measured by ELISA. Results In MLN, dams from the buttermilk and placebo groups had a higher production of IL-10 after both ConA and OVA stimulation and a higher proportion of helper T cells expressing co-inhibitory marker (CD4+CD152+) when compared to the control diet (both P < 0.05). No changes were found in IL-2, TNF-α, or IL-6 production and the proportion of regulatory T cells (CD3+CD4+CD25+FoxP3+) among groups. In PP, dams from the buttermilk group had a higher proportion of CD45RA + cells (B cells) compared to both the placebo and control diets and dams from the placebo diet had a higher proportion of dendritic cells (DC, OX62+OX6+) compared to both the buttermilk and control diets (both P < 0.05). Conclusions Compared to the control diet (only FC), the buttermilk and placebo diets appear to beneficially modulate oral tolerance by increasing the production of IL-10 (an important mediator) and could be partially explain by the higher proportion of CD4+CD152+cells in MLN. In PP, the higher proportion of B cells in the buttermilk and DC in the placebo groups, suggests that dams from these groups may have better antigen presentation function, which may further assist the induction of oral tolerance. Funding Sources Dairy Farmers of Canada, NSERC, CONACYT.

Download Full-text

CLEC10A is a Potential Prognostic Biomarker and Immune Regulator of Tumor Microenvironment in Breast Cancer

10.21203/rs.3.rs-295872/v1 ◽

2021 ◽

Author(s):

Jincheng He ◽

Lei Jiang ◽

Jun Wang ◽

Guangtao Min ◽

Xiangwen Wang ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

B Cells ◽

Tumor Microenvironment ◽

Immune Cells ◽

Cox Regression ◽

Clinical Stage ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cox Regression Analysis

Abstract The communication between tumor cells and immune cells influences the ecology of the tumor microenvironment in breast cancer, as well as the disease progression and clinical outcome. The aim of this study was to investigate the prognostic value of the immunomodulatory factor CLEC10A in breast cancer. We applied the CIBERSORT and ESTIMATE calculation methods to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal components in 1053 BRCA cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, CLEC10A was identified as a prognostic factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that CLEC10A expression was negatively correlated with the clinical pathologic characteristics (age, clinical stage) and positively correlated with survival of BRCA patients. Gene set enrichment analysis (GSEA) showed that genes in the high CLEC10A expression group were mainly enriched in immune-related activities. Genes in the low CLEC10A expression group were enriched in biochemical functions. CIBERSORT analysis of the proportion of TICs revealed that Macrophages M1, B cells memory, B cells naive, T cells CD4+ memory activated, T cells CD8+, and T cells gamma delta were positively correlated with CLEC10A expression, and Macrophages M0, Macrophages M2, Neutrophils, and NK cells resting were positively correlated with CLEC10A expression was negatively correlated, suggesting that CLEC10A may be an important factor in the immune regulation of the tumor microenvironment, especially in mediating the anti-tumor immune response of tumor-infiltrating immune cells at the tumor initiation stage. Therefore, CLEC10A expression may contribute to the prognosis of BRCA patients and provide a new idea for the immunotherapy of BRCA.

Download Full-text

Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis

Cells ◽

10.3390/cells10113116 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3116

Author(s):

Tobias Moser ◽

Lena Hoepner ◽

Kerstin Schwenker ◽

Michael Seiberl ◽

Julia Feige ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

B Cells ◽

Cell Surface ◽

Mode Of Action ◽

Immune Cell ◽

Cell Surface Molecules ◽

Surface Molecules ◽

Surface Patterns ◽

The Impact

Cladribine (CLAD) is a deoxyadenosine analogue prodrug which is given in multiple sclerosis (MS) as two short oral treatment courses 12 months apart. Reconstitution of adaptive immune function following selective immune cell depletion is the presumed mode of action. In this exploratory study, we investigated the impact of CLAD tablets on immune cell surface molecules for adhesion (CAMs) and costimulation (CoSs) in people with MS (pwMS). We studied 18 pwMS who started treatment with CLAD and 10 healthy controls (HCs). Peripheral blood mononuclear cells were collected at baseline and every 3 months throughout a 24-month period. We analysed ICAM-1, LFA-1, CD28, HLADR, CD154, CD44, VLA-4 (CD49d/CD29), PSGL-1 and PD-1 with regard to their expression on B and T cells (T helper (Th) and cytotoxic T cells (cT)) and surface density (mean fluorescence intensity, MFI) by flow cytometry. The targeted analysis of CAM and CoS on the surface of immune cells in pwMS revealed a higher percentage of ICAM-1 (B cells, Th, cT), LFA-1 (B cells, cT), HLADR (B cells, cT), CD28 (cT) and CD154 (Th). In pwMS, we found lower frequencies of Th and cT cells expressing PSGL-1 and B cells for the inhibitory signal PD-1, whereas the surface expression of LFA-1 on cT and of HLADR on B cells was denser. Twenty-four months after the first CLAD cycle, the frequencies of B cells expressing CD44, CD29 and CD49d were lower compared with the baseline, together with decreased densities of ICAM-1, CD44 and HLADR. The rate of CD154 expressing Th cells dropped at 12 months. For cT, no changes were seen for frequency or density. Immune reconstitution by oral CLAD was associated with modification of the pro-migratory and -inflammatory surface patterns of CAMs and CoSs in immune cell subsets. This observation pertains primarily to B cells, which are key cells underlying MS pathogenesis.

Download Full-text

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

10.21203/rs.3.rs-57690/v1 ◽

2020 ◽

Author(s):

Jieqiong Liu ◽

Ying Li ◽

Qian Li ◽

Dandan Liang ◽

Quanren Wang ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

B Cells ◽

Phase Ii ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Cell ◽

Objective Response ◽

Blood Samples ◽

Lower Baseline

Abstract Background: We recently reported the results of a phase II clinical trial that the combinational use of camrelizumab plus apatinib induced an objective response rate (ORR) at 43.3% in advanced triple-negative breast cancer (TNBC) patients. This study presents the analysis of potential tumor and blood biomarkers for the patients responded to the combinational therapy. Methods: Stromal tumor-infiltrating lymphocytes (TILs), CD8+ T cells and the protein expression of programmed death protein 1 (PD-1) and PD-L1 were evaluated in tumor samples collected before and after the treatment. Peripheral blood samples were collected before treatment, 2-weeks and 8-weeks after treatment. 59 cytokines/chemokines, growth factors, or checkpoint-related proteins, blood immune cell subpopulations were analyzed in the blood samples. The correlation between biomarkers and clinical outcomes including ORR, progression-free survival (PFS), and overall survival (OS) was analyzed. Results: Upon database lock, the ORR of 28 evaluable patients was 46.4%. An increase of tumor-infiltrating CD8+ T cells more than 15% during therapy was significantly associated with higher ORR (P=0.040). Patients with lower baseline plasma levels of HGF or IL-8 were more likely to respond to the combinational treatment (P=0.005 or 0.001, respectively), and showed a longer PFS and OS (HGF: PPFS<0.0001, POS<0.0001; IL-8: PPFS<0.0001, POS=0.009). Patients with a decrease of IL-8, or an increase of TIM-3 or CD152 during treatment responded more to the treatment (P=0.008, 0.040, or 0.014, respectively). Responders had a higher baseline CD4+ T cells and B cell proportions in blood than non-responders (P=0.002 and 0.030 respectively). Moreover, patients with higher baseline CD4+ T cells or B cells proportions in blood showed a longer PFS (P<0.001) or a longer OS (P=0.030) respectively. Conclusion: Higher baseline TILs or a greater increase of tumor-infiltrating CD8+ T cells during therapy, lower baseline plasma HGF/IL-8, a decrease of plasma IL-8, an increase of plasma TIM-3/CD152 during therapy, higher baseline CD4+ T cells or B cells proportion in blood are potential biomarkers for the combinational anti-angiogenesis and immunotherapy in advanced TNBC patients.

Download Full-text