Immune System In Breast Cancer Research Articles

The differential effect of the immune system in breast cancer

Cancer cure with immunotherapy is an innovative step towards cancer treatment with better survivability, but it is mostly dependent on the response of the patient’s immune system to the immunotherapeutic approach. This descriptive review article emphasizes the conventional and advanced treatment modalities currently available for breast cancer management. This review also highlights the clinical management of breast cancer concerning immune response especially to unravel the prospects for manipulation of immune cells: such as lymphocytes, including T-cells, T-regulatory cells and natural killer cells, and others like macrophages, dendritic cells, and the panel of interleukins or interferons released by them which has made a significant impact on breast cancer research. In addition, an effort was made to emphasize the different clinical trials and their future implication for the reduction of breast cancer cases. Overall, an attempt has been made to shed light on the possibilities of immunotherapeutics in breast cancer care, as well as the role of immune response in the incidence, aggressiveness, and survival of breast cancer.

Unveiling the Immune Microenvironment's Role in Breast Cancer: A Glimpse into Promising Frontiers.

Breast cancer (BC), one of the most widespread and devastating diseases affecting women worldwide, presents a significant public health challenge. This review explores the emerging frontiers of research focused on deciphering the intricate interplay between BC cells and the immune microenvironment. Understanding the role of the immune system in BC is critical as it holds promise for novel therapeutic approaches and precision medicine strategies. This review delves into the current literature regarding the immune microenvironment's contribution to BC initiation, progression, and metastasis. It examines the complex mechanisms by which BC cells interact with various immune cell populations, including tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Furthermore, this review highlights the impact of immune-related factors, such as cytokines and immune checkpoint molecules. Additionally, this comprehensive analysis sheds light on the potential biomarkers associated with the immune response in BC, enabling early diagnosis and prognostic assessment. The therapeutic implications of targeting the immune microenvironment are also explored, encompassing immunotherapeutic strategies and combination therapies to enhance treatment efficacy. The significance of this review lies in its potential to pave the way for novel therapeutic interventions, providing clinicians and researchers with essential knowledge to design targeted and personalized treatment regimens for BC patients.

Hypoxia-driven ncRNAs in breast cancer.

Low oxygen tension, or hypoxia is the driving force behind tumor aggressiveness, leading to therapy resistance, metastasis, and stemness in solid cancers including breast cancer, which now stands as the leading cause of cancer-related mortality in women. With the great advancements in exploring the regulatory roles of the non-coding genome in recent years, the wide spectrum of hypoxia-responsive genome is not limited to just protein-coding genes but also includes multiple types of non-coding RNAs, such as micro RNAs, long non-coding RNAs, and circular RNAs. Over the years, these hypoxia-responsive non-coding molecules have been greatly implicated in breast cancer. Hypoxia drives the expression of these non-coding RNAs as upstream modulators and downstream effectors of hypoxia inducible factor signaling in the favor of breast cancer through a myriad of molecular mechanisms. These non-coding RNAs then contribute in orchestrating aggressive hypoxic tumor environment and regulate cancer associated cellular processes such as proliferation, evasion of apoptotic death, extracellular matrix remodeling, angiogenesis, migration, invasion, epithelial-to-mesenchymal transition, metastasis, therapy resistance, stemness, and evasion of the immune system in breast cancer. In addition, the interplay between hypoxia-driven non-coding RNAs as well as feedback and feedforward loops between these ncRNAs and HIFs further contribute to breast cancer progression. Although the current clinical implications of hypoxia-driven non-coding RNAs are limited to prognostics and diagnostics in breast cancer, extensive explorations have established some of these hypoxia-driven non-coding RNAs as promising targets to treat aggressive breast cancers, and future scientific endeavors hold great promise in targeting hypoxia-driven ncRNAs at clinics to treat breast cancer and limit global cancer burden.

Ginsenoside Rh4 inhibits breast cancer growth through targeting histone deacetylase 2 to regulate immune microenvironment and apoptosis

High expression of histone deacetylase 2 (HDAC2) is recognized as a marker of invasive breast cancer (BC). HDAC2 is not only responsible for enhancing tumor cell growth, development, and anti-apoptosis, but also plays a significant role in regulating PD-L1 on the surface of tumor cells. Continuous expression of PD-L1 allows tumor cells to escape immune surveillance. There is not much research on how HDAC2 affects the immune system in breast cancer. Ginsenoside Rh4 (Rh4) is a major rare saponin in heat-treated ginseng, which is widely applied in treating and preventing various diseases because of its potent medicinal value and stable safety. However, it is unclear how Rh4 affects the tumor immune microenvironment in breast cancer. Therefore, this paper aims to investigate the effect of Rh4 on HDAC2 in breast cancer, specifically the effect of HDAC2 on apoptosis and the immune microenvironment to inhibit breast cancer growth. According to our study, ginsenoside Rh4 has been shown to significantly suppress breast cancer cell proliferation without any adverse effects. The molecular docking results of Rh4 and HDAC2 indicate a binding energy of −6.06 kcal/mol, suggesting the potential of Rh4 as a targeting modulator of HDAC2. Mechanistically, Rh4 induces apoptosis of breast cancer cells by the HDAC2-mediated caspase pathway and inhibits the HDAC2-mediated JAK/STAT pathway to regulate the immune microenvironment, which inhibits breast cancer growth. Specifically, Rh4 was shown for the first time to blockade immune checkpoints (PD-1/PD-L1) and increase levels of T-lymphocytes in the tumor. In a word, our study establishes a theoretical framework for applying Rh4 as an immune checkpoint inhibitor as part of breast cancer treatment.

Insight into the Crosstalk between Photodynamic Therapy and Immunotherapy in Breast Cancer.

Breast cancer (BC) is the world's second most frequent malignancy and the leading cause of mortality among women. All in situ or invasive breast cancer derives from terminal tubulobular units; when the tumor is present only in the ducts or lobules in situ, it is called ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS). The biggest risk factors are age, mutations in breast cancer genes 1 or 2 (BRCA1 or BRCA2), and dense breast tissue. Current treatments are associated with various side effects, recurrence, and poor quality of life. The critical role of the immune system in breast cancer progression/regression should always be considered. Several immunotherapy techniques for BC have been studied, including tumor-targeted antibodies (bispecific antibodies), adoptive T cell therapy, vaccinations, and immune checkpoint inhibition with anti-PD-1 antibodies. In the last decade, significant breakthroughs have been made in breast cancer immunotherapy. This advancement was principally prompted by cancer cells' escape of immune regulation and the tumor's subsequent resistance to traditional therapy. Photodynamic therapy (PDT) has shown potential as a cancer treatment. It is less intrusive, more focused, and less damaging to normal cells and tissues. It entails the employment of a photosensitizer (PS) and a specific wavelength of light to create reactive oxygen species. Recently, an increasing number of studies have shown that PDT combined with immunotherapy improves the effect of tumor drugs and reduces tumor immune escape, improving the prognosis of breast cancer patients. Therefore, we objectively evaluate strategies for their limitations and benefits, which are critical to improving outcomes for breast cancer patients. In conclusion, we offer many avenues for further study on tailored immunotherapy, such as oxygen-enhanced PDT and nanoparticles.

Variable Intrinsic Expression of Immunoregulatory Biomarkers in Breast Cancer Cell Lines, Mammospheres, and Co-Cultures.

Advances in immunotherapy have increased interest in knowing the role of the immune system in breast cancer (BC) pathogenesis. Therefore, immune checkpoints (IC) and other pathways related to immune regulation, such as JAK2 and FoXO1, have emerged as potential targets for BC treatment. However, their intrinsic gene expression in vitro has not been extensively studied in this neoplasia. Thus, we evaluated the mRNA expression of tumor-cell-intrinsic CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FoXO1 in different BC cell lines, derived mammospheres, and co-cultures with peripheral blood mononuclear cells (PBMCs) by real-time quantitative polymerase chain reaction (qRT-PCR). Our results showed that intrinsic CTLA-4, CD274 (PD-L1), and PDCD1LG2 (PD-L2) were highly expressed in triple-negative cell lines, while CD276 was predominantly overexpressed in luminal cell lines. In contrast, JAK2 and FoXO1 were under-expressed. Moreover, high levels of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), and JAK2 were found after mammosphere formation. Finally, the interaction between BC cell lines and peripheral blood mononuclear cells (PBMCs) stimulates the intrinsic expression of CTLA-4, PCDC1 (PD1), CD274 (PD-L1), and PDCD1LG2 (PD-L2). In conclusion, the intrinsic expression of immunoregulatory genes seems very dynamic, depending on BC phenotype, culture conditions, and tumor-immune cell interactions.

Features of the State of Cellular and Humoral Markers of the Immune System in Breast Cancer among Women in Aktobe Region

Features of the State of Cellular and Humoral Markers of the Immune System in Breast Cancer among Women in Aktobe Region

Emerging advances in nanomedicine for breast cancer immunotherapy: opportunities and challenges.

Breast cancer is one of the most common causes of cancer-related morbidity and mortality in women worldwide. Early diagnosis and an appropriate therapeutic approach for all cancers are climacterics for a favorable prognosis. Targeting the immune system in breast cancer is already a clinical reality with notable successes, specifically with checkpoint blockade antibodies and chimeric antigen receptor T-cell therapy. However, there have been inevitable setbacks in the clinical application of cancer immunotherapy, including inadequate immune responses due to insufficient delivery of immunostimulants to immune cells and uncontrolled immune system modulation. Rapid advancements and new evidence have suggested that nanomedicine-based immunotherapy may be a viable option for treating breast cancer.

Atlas of immune cell infiltration in breast cancer—high M2 macrophage and low native B cellproportions are associated with poor survival

Background: Knowledge of the tumor immune microenvironment is critical for developing new treatments targeting the immune system in breast cancer. However, no profile of immune cell infiltration in breast cancer has been provided. The aim of this study is to illustrate an atlas of the immune cell microenvironment of breast cancer.

Immunotherapy using PD-1/PDL-1 inhibitors in metastatic triple-negative breast cancer: A systematic review.

Breast cancer is the most commonly diagnosed cancer in women and is one of the leading causes of death from cancer in women worldwide. Despite the significant benefits of using conventional chemotherapy in the treatment of breast cancer, one of its subtypes, the triple-negative breast cancer, is still a challenge in clinical practice. Recent studies have been investigating the role of the immune system in breast cancer and the development of immunotherapy. Although recently the use of atezolizumab, an anti-PD-L1 monoclonal antibody, combined with chemotherapy was approved, an important step in the treatment of patients with triple-negative metastatic breast cancer, the use of immunotherapy to treat breast tumors remains a major challenge. In this systematic literature review, following PRISMA guidelines, we searched for clinical trials using immunotherapy in the treatment of metastatic triple-negative breast cancer published until March 2020 in the databases EMBASE, PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), with no language restrictions. We did not contact the authors of the clinical trials to obtain additional information. Two researchers independently collected the data and assessed the quality of this study. The literature shows that immunotherapy with anti-PD-1/PD-L1 agents is emerging as a new treatment option in breast cancer. On the other hand, when compared to other types of cancer in which several agents have already been approved, the research is still in its infancy. The use of anti-PD-1/PD-L1 agents as monotherapy revealed encouraging results in the metastatic setting, especially when administered in the early course of the disease, although combination strategies with chemotherapy appear to increase its efficacy. The main limitation of this study is the approach of cancer only in advanced stages.

The Leptin Axis and Its Association With the Adaptive Immune System in Breast Cancer.

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

Immunomodulating Therapies in Breast Cancer-From Prognosis to Clinical Practice.

Simple SummaryThe role of the immune system in breast cancer has been debated for decades. It is generally accepted that tumor-infiltrating lymphocytes are associated with positive prognostic and predictive effects, especially in triple negative breast cancer. This subset of breast cancer is characterized by the absence of hormone receptors and human epidermal growth factor receptor 2. Compared to other breast cancer subtypes, triple-negative breast cancer has more mutations and neoantigens, making it more immunogenic. Releasing the brakes on the immune system with the help of so-called immune checkpoint inhibitors leads to activation of the immune system and destruction of cancer cells. This, in turn, improves survival, especially in early and advanced triple-negative breast cancer. A new and promising strategy is the enhancement of the immune response using individualized mRNA vaccines against tumor-specific neoantigens.The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

157P Moderate physical activity (MPA) modulates immune system in breast cancer (BC) patients during preoperative chemotherapy: The NEO-RUNNER study

There is a link between PA and the immune system. Immune mechanisms activated by PA in BC have not been fully investigated. We analysed the effect of MPA, nordic or fit walking, during neoadjuvant chemotherapy (NACT) in BC patients (pts).

Immunotherapy: New insights in breast cancer treatment.

Breast cancer being the most malignant and lethal disease persistent among women globally. Immunotherapy as a new treatment modality has emerged in understanding the loopholes in the treatment of breast cancer which is mainly attributed to the potential of tumor cells to evade and survive the immune response by developing various strategies. Therefore, improved understanding of the immune evasion by cancer cells and the monoclonal antibodies against PD- and PD-L1 can help us in the diagnosis of this malignancy. Here in this article, I have highlighted that in addition to focusing on other strategies for breast cancer treatment, the involvement of immune system in breast cancer is vital for the understanding of this malignancy. Further, the complete involvement of immune system in the relapse or recurrence of the breast tumor and have also highlighted the role of vaccines, PD-1 and CTLA-4 with the recent advances in the field. Moreover, in addition to the application of immunotherapy as a sole therapy, combinations of immunotherapy with various strategies like targeting it with MEK inhibitors, Vaccines, chemotherapy and PARP inhibitor has shown to have significant benefits is also discussed in this article.

The contradictory functions of NLRX1 in breast cancer allow for suppression or promotion of tumor growth and metastasis in a cell-specific manner.

Abstract Breast cancer is a deadly malignancy that is responsible for 15% of all cancer-related deaths in women. Examining the innate immune system in breast cancer has revealed the importance of pattern recognition receptors, such as NLRX1, in disease progression. NLRX1 has been implicated as a tumor suppressor because it suppresses inflammation by many mechanisms, including by inhibiting the NF-κB pathway. Here, we investigated the potential of NLRX1 as a tumor suppressor in breast cancer when it is expressed either by healthy host cells or cancer cells. To determine the role of NLRX1 in healthy host cells, we used the 4T1 breast cancer model in WT and Nlrx1−/− (KO) mice. KO mice exhibited increased lung metastasis and tumor size compared to WT mice. Gene expression data revealed increased expression of proliferation, survival, growth, invasion, and metastatic genes in tumors from KO mice compared to WT mice. Thus, NLRX1 in healthy host cells is protective against breast cancer tumor growth and metastasis. Next, we investigated the role of NLRX1 in breast cancer cells. 4T1 cells were transduced to overexpress NLRX1 and injected into WT (WTOE) and KO(KOOE) mice. Transduction controls were also generated and injected into WT (WTOE-CTL) and KO (KOOE-CTL) mice. KOOE mice developed larger tumors than KOOE-CTL mice. KOOE mice also developed more lung metastasis compared to WTOE, WTOE-CTL, and KOOE-CTL mice. This suggests NLRX1 in breast cancer cells contributes to tumor growth and metastasis, which directly contradicts the function of NLRX1 in healthy host cells and demonstrates a cell-specific function of NLRX1 in breast cancer. These cell-specific differences are critical foundations for the development of NLR-based breast cancer therapies.

Possible Diagnostic Application of CXCL12 and CXCR4 as Tumor Markers in Breast Cancer Patients.

Chemokines are cytokines involved not only in inflammatory but also in inappropriate response of the immune system in breast cancer (BC) progression. We examined the diagnostic usefulness of CXCL12, CXCR4 and CA 15-3 in BC patients, based on ROC curve analysis. The study group consisted of 100 patients with BC; the control group consisted of 35 women with benign breast disease and 35 healthy patients. The median concentration of chemokines was measured by ELISA and that of CA 15-3 by chemiluminescent microparticle immunoassay. The concentrations of CXCL12 and CXCR4 in the BC group were significantly higher than those in the control groups. The AUC value of CXCL12 (0.7502) was the highest of all the chemokines measured in the BC patients. There may be a link between CXCL12, CXCR4 and BC that can assist in the diagnosis, markedly when combined with CA 15-3.

Characterization of the relationship between FLI1 and immune infiltrate level in tumour immune microenvironment for breast cancer.

Breast cancer is the most common cancer and the leading cause of cancer death among women in the world. Tumour‐infiltrating lymphocytes were defined as the white blood cells left in the vasculature and localized in tumours. Recently, tumour‐infiltrating lymphocytes were found to be associated with good prognosis and response to immunotherapy in tumours. In this study, to examine the influence of FLI1 in immune system in breast cancer, we interrogated the relationship between the FLI1 expression levels with infiltration levels of 28 immune cell types. By splitting the breast cancer samples into high and low expression FLI1 subtypes, we found that the high expression FLI1 subtype was enriched in many immune cell types, and the up‐regulated differentially expressed genes between them were enriched in immune system processes, immune‐related KEGG pathways and biological processes. In addition, many important immune‐related features were found to be positively correlated with the FLI1 expression level. Furthermore, we found that the FLI1 was correlated with the immune‐related genes. Our findings may provide useful help for recognizing the relationship between tumour immune microenvironment and FLI1, and may unravel clinical outcomes and immunotherapy utility for FLI1 in breast cancer.

151P - Peripheral cytotoxic T cell correlates with tumor mutational burden and is predictive for progression free survival in advanced breast cancer

BackgroundThe clinical relevance of the host immune system in breast cancer has long been studied. Peripheral blood lymphocytes show a great potential due to the advantages of minimal invasiveness, ease of access and high homogeneity. Peripheral blood lymphocytes consists of varying subpopulations. Each subpopulation of peripheral lymphocytes plays a different part in anti-tumor immunity and thus may have different clinical relevance. However, the related studies have rarely been reported. MethodsA total of 264 advanced breast cancer patients (ABCs) were consecutively recruited at our center between January 2015 and September 2018. All patients received the conventional regimen for advanced breast cancer. Detection of peripheral blood lymphocytes at baseline was accomplished in all 264 patients with 118 patients having ctDNA detection simultaneously. The median survival was estimated by Kaplan-Meier curve, with difference detection by log-rank test and Cox proportional hazards regression model. ResultsThe median follow-up time of the study was 13.0 months. Multivariate analysis confirmed that cytotoxic T cell (CTL) was an independent prognostic factor of PFS (P=0.024). Pierson correlation analysis showed one and only positive correlation between tumor mutational burden (TMB) and CTL level at baseline (P=0.015). Furthermore, baseline CTL level was only confirmed in the HER2-positive subgroup (P<0.001) but not in the HR-positive (P=0.333) or in the TNBC subgroup (P=0.322). For the entire cohort, the TMB high (>75%) group had a signifiantly shorter PFS (P=0.004) than TMB low. In the HER2-positive subgroup, the PFS of the TMB high group was shorter than for the TMB low group (P<0.001). We further use survival data obtained from the TCGA database as a validation set to confirm our findings. As expected, 24 out of 105 HER2-positive patients with TMB high were found to have shorter PFS than TMB low (HR=0.2, 95% CI: 0.06∼0.71, P=0.005). ConclusionsPheripheral CTL to total lymphocyte proportion is predictive for PFS in HER2-positive ABCs but not in TNBC or HR positive. Since CTL proportion was found to positively correlate with TMB and high TMB indicates shorter PFS. Thus, the negative prognositc role of CTL was, at least, partly due to the TMB of ABCs. Legal entity responsible for the studyPeking University Cancer Hospital-Beijing Cancer Hospital. FundingNational Natural Science Foundation of China. DisclosureAll authors have declared no conflicts of interest.

Alterations of Signaling Pathways Related to the Immune System in Breast Cancer: New Perspectives in Patient Management.

In recent years, immune manipulation for cancer treatment, including breast cancer, has been increasingly gaining consent, and many attempts have been made, mainly by either strengthening the immune response (IR) or by inhibiting immune evasion. Therefore, elucidating the related mechanisms is of importance due to the potential to improve the management of cancer patients by immunotherapy. This review article summarized some recent experimental studies, which have discovered novel alterations of signaling pathways related to the immune system in breast cancer. These altered signaling pathways have been grouped according to the general biological mechanism involved: tumor-initiating cells (TICs), cancer stem cells (CSCs), immune evasion, tumor growth and progression, prediction of clinical outcome and prediction of response, or resistance to chemotherapy. These altered pathways related to the immune system open clinical opportunities for the prognosis or treatment of patients. Many of these pathways are related to the origin of breast cancer and immune evasion. We recommended development of new drugs which act on these molecular pathways, and the designing of clinical trials to be carried out mainly in breast cancer patients who required adjuvant treatment.

Abstract 5295: Toward high throughput immune infiltrate analysis from H&amp;E stained images

Abstract Our appreciation of the immune system in breast cancer is rapidly evolving. New methods to quantify the composition and spatial distribution of the immune infiltrate from pathology images are urgently needed to develop better strategies to activate the anti-tumor immune response. Existing methods to quantify the immune infiltrate are tedious (manual counting) or rely on immunohistochemistry (IHC) staining to identify immune cells. While significant efforts are underway to develop machine learning tools to categorize cells based on morphologic features in hematoxylin and eosin (H&amp;E) stained histopathology images, all approaches are limited by the scarcity of large, annotated ground truth training sets. In this work, we propose a new approach, leveraging “style-transfer” algorithms from the computer vision community to generate large quantities of training data from IHC stains. Using style transfer, we generate synthetic H&amp;E images from IHC stains for immune markers, such as CD45, CD8 and CD4. The generated images have pixel-perfect ground truth provided by IHC, and do not need manual labeling. We investigate the impact of training on increasing numbers of synthesized images and validate our algorithms on an independent test set annotated by a pathologist (n=100 patients, 3064 identified lymphocytes). Our baseline classifier achieves a 83% accuracy, compared to the pathologist ground truth. This work provides a novel, tractable, and efficient way to train data-hungry algorithms to identify multiple cell types from H&amp;E stained images. This work is supported by a grant from the Breast Cancer Research Foundation (BCRF-17-002) Citation Format: Rishi R. Rawat, Daniel Ruderman, David B. Agus. Toward high throughput immune infiltrate analysis from H&amp;E stained images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5295.