Immune Microenvironment In Breast Cancer Research Articles

Engineering exosomes to reshape the immune microenvironment in breast cancer: Molecular insights and therapeutic opportunities.

Breast cancer remains a global health challenge, necessitating innovative therapeutic approaches. Immunomodulation and immunotherapy have emerged as promising strategies for breast cancer treatment. Engineered exosomes are the sort of exosomes modified with surface decoration and internal therapeutic molecules. Through suitable modifications, engineered exosomes exhibit the capability to overcome the limitations associated with traditional therapeutic approaches. This ability opens up novel avenues for the development of more effective, personalized, and minimally invasive interventions. In this comprehensive review, we explore the molecular insights and therapeutic potential of engineered exosomes in breast cancer. We discuss the strategies employed for exosome engineering and delve into their molecular mechanisms in reshaping the immune microenvironment of breast cancer. By elucidating the contribution of engineered exosomes to breast cancer immunomodulation, this review underscores the transformative potential of this emerging field for improving breast cancer therapy. Surface modification of exosomes can improve the targeting specificity. The engineered exosome-loaded immunomodulatory cargo regulates the tumour immune microenvironment. Engineered exosomes are involved in the immune regulation of breast cancer.

Decreased LDHB expression in breast tumor cells causes NK cell activation and promotes tumor progression.

Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B (LDHB) has been detected in breast cancer but the function of LDHB remains unknown. Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer (NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation. In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers. Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a therapeutic target for breast cancer.

Evaluating immunotherapeutic outcomes in triple negative breast cancer with a cholesterol radiotracer in mice.

Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement of cholesterol for activation and function of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged the PET radiotracer, eFNP-59. eFNP-59 is an analog of cholesterol that our group validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing ICI-responsive and non-responsive tumors directly, uptake of fluorescent cholesterol and eFNP-59 increased in T cells from ICI-responsive tumors. We discovered that accumulation of cholesterol by T cells increased in ICI-responding tumors that received anti-PD-1 checkpoint immunotherapy. In patients with TNBC, tumors containing cycling T cells had features of cholesterol uptake and trafficking within those populations. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells detects T cell activation and has potential to assess the success of ICI therapy.

Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

Estrogen receptor regulation of the Immune Microenvironment in Breast Cancer

Breast cancer (BCa) is the most common cancer in women and the estrogen receptor (ER)+ subtype is increasing in incidence. There are numerous therapy options available for patients that target the ER, however issues such as innate and acquired treatment resistance, and treatment related side effects justify research into alternative therapeutic options for these patients. Patients of many solid tumour types have benefitted from immunotherapy, however response rates have been generally low in ER+ BCa. We summarise the recent work assessing CDK4/6 inhibitors for ER+ BCa and how they have been shown to prime anti-tumour immune cells and achieve impressive results in preclinical models. A great example of how the immune system might be activated against ER+ BCa. We review the role of estrogen signalling in immune cells, and explore recent data highlighting the hormonal regulation of the immune microenvironment of normal breast, BCa and immune disorders. As recent data has indicated that macrophages are particularly susceptible to estrogen signalling, we highlight macrophage phagocytosis as a key potential target for priming the tumour immune microenvironment. We challenge the generally accepted paradigm that ER+ BCa are "immune-cold" - advocating instead for research into therapies that could be used in combination with targeted therapies and/or immune checkpoint blockade to achieve durable antitumour responses in ER+ BCa.

297 (PB-113) Poster - Insights into HER2-Low Status and the Breast Cancer Immune Microenvironment: A 20-Gene Signature Study

297 (PB-113) Poster - Insights into HER2-Low Status and the Breast Cancer Immune Microenvironment: A 20-Gene Signature Study

The Role of CD8A in the Immune Microenvironment of Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer (BC), and it is often associated with a high tumor grade, a younger age at diagnosis, and a low survival rate. Conventional endocrine and anti-HER-2 therapies are usually ineffective against TNBC, creating treatment challenges and resulting in a poor prognosis. Hence, new targets and treatment strategies for TNBC are urgently required. The GSE102818 dataset was used to identify differentially expressed genes (DEGs) between primary BC and metastatic BC lesions. The Cancer Genome Atlas and the cBioPortal platform were employed to explore mutations in candidate genes. Utilizing the Tumor IMmune Estimation Resource (TIMER), the relationship between the expression of candidate genes and immune cell infiltration was assessed. Additionally, the cell-specific expression of the candidate genes was examined in the immune microenvironment of primary BC and metastatic BC lesions using the single-cell RNA sequencing (scRNA-seq) datasets GSE118389 and GSE202695. Finally, the protein expression of the candidate genes in clinical TNBC samples was evaluated. CD8A was identified as a hub gene in the DEG network and was found to be down-regulated in metastatic BC lesions. CD8A expression was highly correlated with the infiltration of CD8+ T cells, and elevated CD8A expression was correlated with improved survival. Interestingly, scRNA-seq data revealed that CD8A was down-regulated in CD8+ T cells in the immune microenvironment of metastatic BC lesions. Finally, the evaluation of clinical samples confirmed the down-regulation of CD8A in the immune microenvironment of BC lung metastases. In patients with metastatic TNBC, high levels of CD8A (especially in the immune microenvironment) are associated with a good prognosis.

Low-density lipoprotein receptor promotes crosstalk between cell stemness and tumor immune microenvironment in breast cancer: a large data-based multi-omics study

BackgroundTumor cells with stemness in breast cancer might facilitate the immune microenvironment’s suppression process and led to anti-tumor immune effects. The primary objective of this study was to identify potential targets to disrupt the communication between cancer cell stemness and the immune microenvironment.MethodsIn this study, we initially isolated tumor cells with varying degrees of stemness using a spheroid formation assay. Subsequently, we employed RNA-seq and proteomic analyses to identify genes associated with stemness through gene trend analysis. These stemness-related genes were then subjected to pan-cancer analysis to elucidate their functional roles in a broader spectrum of cancer types. RNA-seq data of 3132 patients with breast cancer with clinical data were obtained from public databases. Using the identified stemness genes, we constructed two distinct stemness subtypes, denoted as C1 and C2. We subsequently conducted a comprehensive analysis of the differences between these subtypes using pathway enrichment methodology and immune infiltration algorithms. Furthermore, we identified key immune-related stemness genes by employing lasso regression analysis and a Cox survival regression model. We conducted in vitro experiments to ascertain the regulatory impact of the key gene on cell stemness. Additionally, we utilized immune infiltration analysis and pan-cancer analysis to delineate the functions attributed to this key gene. Lastly, single-cell RNA sequencing (scRNA-seq) was employed to conduct a more comprehensive examination of the key gene’s role within the microenvironment.ResultsIn our study, we initially identified a set of 65 stemness-related genes in breast cancer cells displaying varying stemness capabilities. Subsequently, through survival analysis, we pinpointed 41 of these stemness genes that held prognostic significance. We observed that the C2 subtype exhibited a higher stemness capacity compared to the C1 subtype and displayed a more aggressive malignancy profile. Further analysis using Lasso-Cox algorithm identified LDLR as a pivotal immune-related stemness gene. It became evident that LDLR played a crucial role in shaping the immune microenvironment. In vitro experiments demonstrated that LDLR regulated the cell stemness of breast cancer. Immune infiltration analysis and pan-cancer analysis determined that LDLR inhibited the proliferation of immune cells and might promote tumor cell progression. Lastly, in our scRNA-seq analysis, we discovered that LDLR exhibited associations with stemness marker genes within breast cancer tissues. Moreover, LDLR demonstrated higher expression levels in tumor cells compared to immune cells, further emphasizing its relevance in the context of breast cancer.ConclusionLDLR is an important immune stemness gene that regulates cell stemness and enhances the crosstalk between breast cancer cancer cell stemness and tumor immune microenvironment.

Construction and validation of a transient receptor potential-related long noncoding RNA signature for prognosis prediction in breast cancer patients.

Breast cancer (BC) is the most commonly diagnosed malignancy in women around the world. Accumulating evidence suggests that transient receptor potential (TRP) channels play a significant role in tumor progression and immune cell infiltration. Hence, we conducted the study to investigate the correlation between TRP-associated lncRNAs and the prognosis of breast carcinoma. In the current study, 33 TRP-associated genes were selected from a review published by Amrita Samanta et al, and the TRP-related lncRNAs were identified by Pearson analysis. Based on the sum of the expression levels of 12 lncRNAs provided by the Cancer Genome Atlas (TCGA), a TRP-associated lncRNA signature was established by using Cox regression analysis. According to the median value of the risk score in the training set, BC patients were separated into high- and low-risk groups. Subsequently, functional enrichment analysis was conducted on the differential expression genes (DEGs) between different risk groups. The Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression (ESTIMATE) Score was calculated by ESTIMATE, and the immune cell infiltration was evaluated by ssGSEA. Finally, the immune checkpoint gene expression levels, microsatellite instability (MSI), and immunophenoscore (IPS) were further assessed. The high-risk groups exhibited lower survival rates, while the low-risk groups showed higher survival rates. As a result, the DEGs between different risk groups were highly enriched in immune cell activation and immunoregulation. Besides, the ESTIMATE scores of patients in low-risk groups were higher than those in high-risk groups. The infiltration levels of several immune cells were remarkably elevated in low-risk groups, and various immune signatures were activated with a decreased risk score. Eventually, the TRP-associated lncRNA signature was confirmed with a highly potential ability to evaluate the immunotherapy response in breast carcinoma patients. The outcomes of the current study indicated that the 12-TRP-associated-lncRNA risk model was an independent prognostic risk factor for BC patients. This risk model could be closely related to the tumor immune microenvironment in BC. Our findings will provide new insights for future immunotherapy for BC treatment.

Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer

BackgroundHistone lysine lactylation (Kla) is a newly identified histone modification, which plays a crucial role in cancer progression. Hence, we determined the prognostic value of Kla in breast cancer (BC).MethodsWe obtained RNA expression profiles of BC from The Cancer Genome Atlas (TCGA), following screening out Kla-specific genes. Furthermore, we determined the prognostic value of Kla by constructing a cox model based on Kla-specific genes. Subsequently, we identified expression of lactate accumulation-related genes and prognostic Kla-specific genes through Human Protein Atlas (HPA), and further performed a correlation analysis based on their expression. Meanwhile, we explored the effects of Kla on BC tumor microenvironment (TME), drug therapy and immunotherapy. Moreover, we predicted the pathways influenced by Kla via gene set enrichment analysis (GSEA).ResultsA total of 1073 BC samples and 112 normal controls were obtained from TCGA, and 23 tumor samples were removed owing to inadequate clinical information. We identified 257 differentially expressed Kla-specific genes (DEKlaGs) in BC. A cox model involved with CCR7, IGFBP6, NDUFAF6, OVOL1 and SDC1 was established, and risk score could be visualized as an independent biomarker for BC. Meanwhile, Kla was remarkably associated with BC immune microenvironment, drug therapy and immunotherapy. Kla was identified to be related to activation of various BC-related KEGG pathways.ConclusionIn conclusion, Kla contributes to drug resistance and undesirable immune responses, and plays a crucial role in BC prognosis, suggesting that Kla was expected to be a new therapeutic target for BC.

Quantifying the impact of immunotherapy on RNA dynamics in cancer

BackgroundCheckpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer...

Identification of an exosome-related signature associated with prognosis and immune infiltration in breast cancer

Exosomes, nanosized vesicles, play a vital role in breast cancer (BC) occurrence, development, and drug resistance. Hence, we proceeded to study the potential prognostic value of exosome-related genes and their relationship to the immune microenvironment in BC. 121 exosome-related genes were provided by the ExoBCD database, and 7 final genes were selected to construct the prognostic signature. Besides, the expression levels of the 7 exosome-related genes were validated by the experiment in BC cell lines. Based on the signature, BC patients from the training and validation cohorts were separated into low- and high-risk groups. Subsequently, the R clusterProfiler package was applied to identify the distinct enrichment pathways between high-risk groups and low-risk groups. The relevance of the tumor immune microenvironment and exosome-related gene risk score were analyzed in BC. Eventually, the different expression levels of immune checkpoint-related genes were compared between the two risk groups. Based on the risk model, the low-risk groups were identified with a higher survival rate both in the training and validation cohorts. A better overall survival was revealed in patients with higher scores evaluated by the estimation of stromal and immune cells in malignant tumor tissues using expression (ESTIMATE) algorithm. Subsequently, BC patients with lower risk scores were indicated by higher expression levels of some immune checkpoint-related genes and immune cell infiltration. Exosomes are closely associated with the prognosis and immune cell infiltration of BC. These findings may contribute to improving immunotherapy and provide a new vision for BC treatment strategies.

Integrative dissection of 5-hydroxytryptamine receptors-related signature in the prognosis and immune microenvironment of breast cancer.

Depression increases the risk of breast cancer recurrence and metastasis. However, there lacks potential biomarkers for predicting prognosis in breast cancer. 5-hydroxytryptamine (5-HT) plays a key role in the pathogenesis and treatment of depression. In this study, we developed a prognostic signature based on 5-HT receptors (5-HTRs) and elucidated its potential immune regulatory mechanisms for breast cancer prognosis. Oncomine, GEPIA, UALCAN, cBioPortal, Kaplan-Meier plotter, and TIMER were used to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of HTRs in breast cancer patients. The model training and validation assays were based on the analyses of GSE1456 and GSE86166. A risk signature was established by univariate and multivariate Cox regression analyses. The transwell assay was utilized to verify the effect of the 5-HTRs expression on breast cancer invasion. Effects of HTR2A/2B inhibitor on CD8+ T cell proliferation and infiltration as well as apoptosis of 4T1 cells in the tumor microenvironment were detected by flow cytometry and TUNEL assay. Zebrafish and mouse breast cancer xenografts were used to determine the effect of HTR2A/2B inhibitor on breast cancer metastasis. The expression levels of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR4, and HTR7 were significantly downregulated in highly malignant breast cancer types. 5-HTRs were significantly associated with recurrence-free survival (RFS) in breast cancer patients. The genetic alteration of HTR1D, HTR3A, HTR3B, and HTR6 in breast cancer patients was significantly associated with shorter overall survival (OS). Finally, HTR2A and HTR2B were determined to construct the risk signature. The expression of HTR2A/2B was positively correlated with the infiltration of immune cells such as CD8+ T cells and macrophages. Furthermore, inhibition of HTR2A expression could suppress CD8+ T cell proliferation and enhance invasion and metastasis of breast cancer cells in both zebrafish and mice model. The HTR2A/2B risk signature not only highlights the significance of HTRs in breast cancer prognosis by modulating cancer immune microenvironment, but also provides a novel gene-testing tool for early prevention of depression in breast cancer patients and lead to an improved prognosis and quality of life.

Integrating Single-Cell RNA-Seq and Bulk RNA-Seq Data to Explore the Key Role of Fatty Acid Metabolism in Breast Cancer.

Cancer immune escape is associated with the metabolic reprogramming of the various infiltrating cells in the tumor microenvironment (TME), and combining metabolic targets with immunotherapy shows great promise for improving clinical outcomes. Among all metabolic processes, lipid metabolism, especially fatty acid metabolism (FAM), plays a major role in cancer cell survival, migration, and proliferation. However, the mechanisms and functions of FAM in the tumor immune microenvironment remain poorly understood. We screened 309 fatty acid metabolism-related genes (FMGs) for differential expression, identifying 121 differentially expressed genes. Univariate Cox regression models in The Cancer Genome Atlas (TCGA) database were then utilized to identify the 15 FMGs associated with overall survival. We systematically evaluated the correlation between FMGs' modification patterns and the TME, prognosis, and immunotherapy. The FMGsScore was constructed to quantify the FMG modification patterns using principal component analysis. Three clusters based on FMGs were demonstrated in breast cancer, with three patterns of distinct immune cell infiltration and biological behavior. An FMGsScore signature was constructed to reveal that patients with a low FMGsScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, better survival advantage, and were more sensitive to immunotherapy than those with a high FMGsScore. Finally, the expression and function of the signature key gene NDUFAB1 were examined by in vitro experiments. This study significantly demonstrates the substantial impact of FMGs on the immune microenvironment of breast cancer, and that FMGsScores can be used to guide the prediction of immunotherapy efficacy in breast cancer patients. In vitro experiments, knockdown of the NDUFAB1 gene resulted in reduced proliferation and migration of MCF-7 and MDA-MB-231 cell lines.

Genomic properties and clinical outcomes associated with tertiary lymphoid structures in patients with breast cancer

Tertiary lymphoid structures (TLSs) play a crucial role in determining prognosis and response to immunotherapy in several solid malignancies. Nevertheless, the effect of TLS-associated gene signature based on The Cancer Genome Atlas (TCGA) cohort in patients with breast cancer (BRCA) remains controversial. Based on TCGA-BRCA dataset (n = 866), 9-gene was identified to construct an TLS signature and further analyzed its prognostic value. Then, we explored the relationship of this TLS signature with molecular subtype, immune microenvironment, tumor mutational burden (TMB). High-TLS signature patients had a better overall survival (OS) than low-TLS signature patients, consistent with the results in the METABRIC cohort. Multivariate analysis revealed that TLS signature remained an independent prognostic indicator for OS. In addition, we established a nomogram with the integration of TLS signature and other independent variables to predict individual risk of death. The comprehensive results showed that patients with high TLS signature benefit from immunotherapy; the signature was also correlated with inhibition of cell proliferation pathways, low TP53 mutation rate, high infiltration of B cells, CD8 + T cells, CD4 + T cells, and M1 macrophages. Therefore, TLS signature is a promising biomarker to distinguish the prognosis and immune microenvironment in BRCA.

Mechanism of breast cancer immune microenvironment in prognosis of heart failure

The treatment of breast cancer can potentially impose a burden on the heart, leading to an increased risk of heart failure. Studies have shown that more than half of breast cancer patients die from non-tumor-related causes, with cardiovascular disease (CVD) being the leading cause of death. However, the underlying mechanism linking breast cancer prognosis and heart failure remains unclear.To investigate this, we conducted an analysis where we compared the differentially expressed genes (DEGs) in early and advanced breast cancer with genes associated with heart failure. This analysis revealed 18 genes that overlapped between the two conditions, with 15 of them being related to immune function. This suggests that immune pathways may play a role in the prognosis of breast cancer patients with heart failure.Using gene expression data from 1260 breast cancer patients, we further examined the impact of these 15 genes on survival time. Additionally, through enrichment analysis, we explored the functions and pathways associated with these genes in relation to breast cancer and heart failure.By constructing a transformer model, we discovered that the expression patterns of these 15 genes can accurately predict the occurrence of heart failure. The model achieved an AUC of 0.86 and an AUPR of 0.91.Moreover, through analysis of single-cell sequencing data from breast cancer patients undergoing PD-1 treatment and experiencing heart failure, we identified a significant number of cell-type-specific genes that were shared between both diseases. This suggests that changes in gene expression in immune cells following breast cancer treatment may be associated with the development of heart failure.

YAP/STAT3 inhibited CD8+ T cells activity in the breast cancer immune microenvironment by inducing M2 polarization of tumor-associated macrophages.

Breast cancer (BC) is the leading cause of cancer-related death among women. One of the hallmarks of cancer is sustained angiogenesis. YAP/STAT3 may promote angiogenesis and driving BC progression. This study aimed to investigate how YAP/STAT3 affects the immune microenvironment in BC and understand the underlying mechanism. To establish a tumor-associated macrophages (TAMs) model, macrophages were cultured in the 4T1 cell culture medium. A BC mouse model was created by injecting 4T1 cells. The expression of YAP, STAT3, p-STAT3, VEGF, VEGFR-2, and PD-L1 was analyzed using immunofluorescence, western blotting, and quantitative real-time PCR. Flow cytometry was used to identify M1 and M2 macrophages, CD4+ T, CD8+ T, and Treg cells. Levels of iNOS, IL-12, IL-10, TGF-β, Arg-1, and CCL-22 were measured using enzyme-linked immunosorbent assay. Co-IP was used to verify whether YAP binds to STAT3. Hematoxylin-eosin staining was used to observe tumor morphology. Cell counting kit-8 was selected to detect T-cell proliferation. YAP, STAT3, P-STAT3, VEGF, VEGFR-2, and PD-L1 were highly expressed in BC tissues. The M2/M1 macrophages ratio increased in the TAMs group compared with the control group. Inhibiting of YAP and STAT3 decreased the M2/M1 macrophages ratio. YAP was found to bind with STAT3. T-cell proliferation was enhanced after YAP inhibition, and overexpression of STAT3 reversed the regulation of YAP on T-cell proliferation. In animal studies, inhibiting YAP inhibited tumor weight and volume development. After YAP inhibition, inflammatory infiltration, M2/M1 macrophage ratio, and Treg cell ratio declined, while CD8+ and CD4+ T-cell ratio increased. In conclusion, this study suggested inhibition of YAP/STAT3 reversed M2 polarization of TAMs and suppressed CD8+ T-cell activity in the BC immune microenvironment. These findings open up new avenues for the development of innovative therapies in the treatment of BC.

The current advances of lncRNAs in breast cancer immunobiology research.

Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related death in women worldwide. Breast cancer development and progression are mainly associated with tumor-intrinsic alterations in diverse genes and signaling pathways and with tumor-extrinsic dysregulations linked to the tumor immune microenvironment. Significantly, abnormal expression of lncRNAs affects the tumor immune microenvironment characteristics and modulates the behavior of different cancer types, including breast cancer. In this review, we provide the current advances about the role of lncRNAs as tumor-intrinsic and tumor-extrinsic modulators of the antitumoral immune response and the immune microenvironment in breast cancer, as well as lncRNAs which are potential biomarkers of tumor immune microenvironment and clinicopathological characteristics in patients, suggesting that lncRNAs are potential targets for immunotherapy in breast cancer.

The impact of exercise training on the pathologic response and tumor immune microenvironment in breast cancer after neoadjuvant chemotherapy: An exploratory study.

e12596 Background: In early breast cancer (BC), pathological complete response (pCR) is an efficacy endpoint of neoadjuvant chemotherapy (ChT) and percentage of tumor-infiltrating lymphocytes (TILs) is a prognostic biomarker. Although exercise training is an evidence-based supportive care across the BC journey, one open question is its impact on the antitumor effect of neoadjuvant ChT. The authors aim to investigate the effects of a supervised exercise training program (STEP) in pCR and TILs in BC women undergoing neoadjuvant ChT. Methods: MAMA_MOVE_Gaia on Treatment (ISRCTN, ISRCTN32617901) is randomized controlled trial in which women with early BC undergoing anthracycline containing ChT were randomized in a 1:1 ratio to a SETP or to usual care, close to recruitment in January 2022. For this exploratory analysis, we retrospectively identified patients who underwent neoadjuvant ChT, and compare pCR and TILs between the two arms. Results: Sixty-four participants were included, aged from 26 to 72 years old (mean = 50.3, SD = 10.1) majority with stage II and III (n = 58, 90,6%) and HER2+ (n = 23, 35.9%) or triple negative (n = 19, 29.7%) disease. The pCR in STEP arm had a prevalence of 56.7% and in the usual care arm of 55.9%(p = 0.950). In the STEP arm median TILs were, for the biopsy and tumor site, of 5.0 (range 0.0-80.0) and 5.0 (range 5.0-30.0). In the usual care arm, median TILs were, for the biopsy and tumor site, of 5.0 (range 0.0-90.0) and 0.0 (range 0.0-30.0). There was no difference between groups for TILs of the biopsy (p = 0.907). Higher TILs of the tumor site was marginally associated with the STEP arm (p = 0.082). Conclusions: Despite the results obtained, it is believed that a larger sample may lead to different results. However, these data could also support future research in this field, bringing new insights for cancer survivors continuum of care.

Potentiated effects of lactate receptor GPR81 on immune microenvironment in breast cancer.

G protein-coupled receptor (GPR81), as lactate receptor, is an upstart in immune regulation, however, its mechanisms involved in tumor escape have not been fully elucidated. In this study, we explored the effects of GPR81 activation on triple-negative breast cancer (TNBC) cells and macrophages. The expression and relationship with immune infiltration of GPR81 were analyzed with TCGA database. Checkpoints and cytokines were evaluated with flow cytometry or ELISA. The TCGA-based data showed a marked decrease of GPR81 in breast cancer (BRCA) compared with normal breast, especially in the basal-like subtype. In normal mammary tissues, GPR81 had negative correlation with various immune checkpoints, nevertheless, this trend weakened accompanied with the reduction of GPR81. GPR81 stimulation had a significantly inhibitory influence on PD-L1 exposure in BT-549 and MDA-MB-231 cell lines, but not in MDA-MB-453 cell line. The pretreatment of siGPR81 to knockdown GPR81 expression resulted in a remitting of PD-L1 reduction when MDA-MB-231 cells were treated with GPR81 agonist 1. However, little effect of GPR81 activation was observed on the expression of PD-L1 on phorbol-12-myristate-13-acetate (PMA)-induced THP-1 cells. Furthermore, GPR81 agonist 1 exerted no significant impact on the secretion of cytokines in THP-1 cells. In general, it is suggested that GPR81 may facilitate immune monitoring via the reduction of PD-L1 in TNBC with glycolytic phenotype. Our results not only provide a novel insight into the effects of GPR81 on immune evasion but a potential therapy targeting GPR81 in BRCA.