Expression Patterns of Immune Checkpoints In Breast Cancer Patients

Abstract Background: immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival (OS). Positive response to PD-1/PD-L1 blockades was observed in the treatment of solidtumors. Breast cancer (BC) patients are no exception. However, the efficacy of immunocheckpoint therapy in BC patients remains poor. A particularly important factor is the lack of studies on the expression patterns of immune checkpoints in BC patients. Method: in this study, the microarray dataset GSE10810 was downloaded from the Gene Expression Database Synthesis (GEO) to analyze the differential expression of BC genes and perform GO and KEGG analysis. Then, we explored theprognostic value of ICs for BC patients by analyzing RNA-seq and mutation data from 657 BC patients from theCancer Genome Atlas (TCGA) database. Next, we analyzed the differences in the expression of relevant immune checkpoints between 1085 BC patients and 291 healthy controls (HC) in the Genotype-Tissue Expression (GTEx) database. Finally, we analyzed the expression levels of IFNγ-R, PD-L1, STAT1, IDO and other genes in MCF-10A, MF-10AT, MCF-7, MDA-MB-231 cell lines.Results: It was found that increased expression of PD-1, PD-L1, STAT1, CTLA-4 was associated with poor OS in BC patients. In addition, co-expression of PD-L1 with PD-1, STAT1or CTLA-4 and co-expression of PD-1 with CTLA-4was related to poor OS. We analyzed associations between the proportionate expression of PD-L1 and PD-1, PD-L1 and STAT1, PD-1 and CTLA-4, PD-1 and LAG3, PD-L1 and CTLA-4 in BC patients, there was significance in correlation in both of the BC patients.The expression of STAT1 in BC patients was compared with that of HC, and it was found that STAT1 was highly expressed in BC patients. Conclusions: our results suggest that transcriptome-based co-expression of STAT1 and PD-L1 is a predictor for poor OS in BC patients, which might provide novel insight into designing combinational targeted therapy for BC.

Download Full-text

Circulating PD-L1 (programmed death-ligand 1) and outcomes in a HER2-positive metastatic breast cancer cohort treated with first-line trastuzumab.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1024 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1024-1024 ◽

Cited By ~ 2

Author(s):

Ayesha Ali ◽

Laura Krecko ◽

Kim Leitzel ◽

Suhail M. Ali ◽

Joseph J. Drabick ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

First Line ◽

Her2 Positive ◽

Breast Cancer Cohort

1024 Background: Recently the immune checkpoint inhibitors (ICIs) have demonstrated efficacy across a wide variety of cancers, but have been less effective in breast cancer. PD-L1 (B7-H1, CD274) is a ligand produced by many tumor cells and some immune cells, and suppresses the T cell immune response. This allows tumor cells to escape immune detection. PD-L1 is used as a companion tumor tissue IHC biomarker for patient selection for some of the FDA-approved ICIs (pembrolizumab), but not for others (nivolumab, atezolizumab). Circulating PD-L1 has been detected in multiple myeloma, renal, lung, and gastric cancer, but not in breast cancer. Here we correlated serum PD-L1 levels with outcome in a HER2-positive metastatic breast cancer cohort treated with trastuzumab. Methods: Pretreatment serum was obtained from 63 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. A novel ELLA microfluidic channel immunoassay platform (ProteinSimple, San Jose, CA) was employed to quantitate serum PD-L1. Serum PD-L1 levels were analyzed using continuous, quartile, and dichotomous (25%, median, and 75%) cutpoints. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: On a continuous basis, patients with higher serum PD-L1 had a significantly reduced PFS (p = 0.045) and overall survival OS (p = 0.004) compared to patients with lower serum PD-L1 levels. Patients with the higher quartiles of serum PD-L1 also trended to have reduced PFS (0.11) and significantly reduced OS (p = 0.015) compared to the lower quartiles of serum PD-L1. Finally, using either the 25th or 75th percentile of serum PD-L1 as dichotomous cutpoint, patients with higher serum PD-L1 had significantly reduced OS (p = 0.04). Conclusions: Higher circulating PD-L1 levels were prognostic for reduced PFS and OS in HER2-positive metastatic breast cancer patients treated with first-line trastuzumab. Circulating PD-L1 deserves further study for prognostic and predictive biomarker utility in larger trials of immune checkpoint inhibitors and other immunotherapies in breast and other cancers. AA, LK contributed equally.

Download Full-text

Risk of SARS-CoV-2 infection and disease in metastatic triple-negative breast cancer patients treated with immune checkpoint inhibitors

Immunotherapy ◽

10.2217/imt-2020-0142 ◽

2020 ◽

Cited By ~ 1

Author(s):

Patrizia Vici ◽

Laura Pizzuti ◽

Eriseld Krasniqi ◽

Andrea Botticelli ◽

Gennaro Ciliberto ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Breast Cancer Patients

Download Full-text

Checkpoint Inhibitors in Breast Cancer - Current Status and Future Directions

Breast Care ◽

10.1159/000486706 ◽

2018 ◽

Vol 13 (1) ◽

pp. 27-31 ◽

Cited By ~ 4

Author(s):

Joachim Bischoff

Keyword(s):

Breast Cancer ◽

T Cell Activation ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Death Receptor ◽

Target Population ◽

Current Status ◽

Immune Checkpoints ◽

Breast Cancer Patients

Antineoplastic agents directly targeting tumor cells have represented the major strategy of systemic anticancer therapy for many years. Nevertheless, overcoming resistance mechanisms remains a great challenge because treatment options are limited in many cases. From this point of view, immunotherapeutic approaches seem promising in a broad spectrum of solid tumors. These include in particular the currently available inhibitors directed against immune checkpoints leading to a significant T-cell activation. To date, the programmed death receptor 1 (PD-1) and its ligand are the most prominent targets in this context. However, the role of checkpoint inhibitors in the treatment of breast cancer is still being debated, and the main focus is on triple-negative breast cancer patients as a target population in many ongoing trials. Moreover, the potential superiority of combinations with other anticancer drugs such as cytotoxics and targeted agents will be discussed.

Download Full-text

Comprehensive Analysis of the Immune Microenvironment Reveals that CD52 is a Marker for Breast Cancer Treatment with Immune Checkpoint Inhibitors

10.21203/rs.3.rs-1078018/v1 ◽

2021 ◽

Author(s):

Qiang Wang ◽

Xuxu Liu ◽

Pengfei Wang ◽

Dankun Luo ◽

Wenqi Gao ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Adaptive Immune Response ◽

Breast Cancer Patients ◽

Immune Microenvironment ◽

Adaptive Immune

Abstract Background:Breast cancer (BC) is one of the most common tumors in women. Recent years, immune checkpoint inhibitors (ICIs) have brought good news to BC patients. Although significant achievements have been made through treatment with ICIs, some people who experience serious immune-related adverse events (IrAEs) are still insensitive to this approach. The response to ICI treatment depends on the type of tumor microenvironment (TME). Methods:WGCNA (weighted gene co-expression network analysis), ESTIMATE algorithm, LASSO regression analysis, survival analysis, functional enrichment analysis are conducted to analyze the BC data in the TCGA database. Immunohistochemistry was used to verify the expression of CD52 in BC.Results:WGCNA and ESTIMATE algorithm found that the CD52 is closely related to the immune microenvironment. CD52 highly expressed in various breast cancer subtypes, and patients with high expression of CD52 have longer survival time. Compared with the low-CD52 group, the high-CD52 group had more immune cell infiltration. TIMER database verification results showed that CD8+ T cells, activated memory CD4 T cells, memory B cells, γδ T cells, and Tregs were positively correlated with CD52 expression, while M2 macrophages were negatively correlated. CD52 can change the trend of TIC (CD8+ T) and tumor-associated macrophage (TAM) infiltration with respect to the survival time of breast cancer patients. Based on the expression of CD52, we explored the relationship between CD52 and the adaptive immune response (AIR). CD52 is a marker of AIR stratification in breast cancer patients. We constructed a CD52-related adaptive immune response gene signature (CD52rAIRGsig) which is an independent prognostic factor for breast cancer and related to genome instability and the immune cells infiltration in the TME. CD52 and CD52rAIRGsig were associated with PD-1 signaling and immune checkpoint inhibitor markers, which proves that patients with high CD52 expression and low risk of CD52rAIRGsig are more suitable for ICI treatment. We then screened chemotherapeutics for personalized medicine based on CD52rAIRGsig. Conclusion:Therefore, we have discovered a new marker to guide the treatment and prognosis of breast cancer patients with ICIs. This provides a combined treatment strategy including different combinations of ICIs combined with chemotherapeutic drugs to treat breast cancer.

Download Full-text

Immune checkpoint inhibitors: review of the existing evidence and challenges in breast cancer

Immunotherapy ◽

10.2217/imt-2020-0283 ◽

2021 ◽

Vol 13 (7) ◽

pp. 587-603

Author(s):

Mobina Jalalvand ◽

Farzaneh Darbeheshti ◽

Nima Rezaei

Keyword(s):

Breast Cancer ◽

Immune System ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Breast Cancer Patients ◽

Body Of Knowledge ◽

Us Fda ◽

Checkpoint Receptors

Cancer initiation and progression are associated with immune system responses. Tumor cells use various tricks to scape of immune system, such as activating immune checkpoint pathways that induce immunosuppressive functions. Among the different immune checkpoint receptors, CTLA-4 and PD-1/PD-L1 are prominent therapeutic targets in different cancers. Although the US FDA has approved some immune checkpoint inhibitors for several cancers, concerning breast cancer still different clinical trials are looking for optimizing efficacy and decreasing immune-related adverse events. This review will discuss the existing body of knowledge with regard to cross-talk between immune system and tumor cells and then explore immune checkpoint-related signaling pathways in the context of breast tumors. Finally, we highlight the application of different immune checkpoint blockers in breast cancer patients.

Download Full-text

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

Cancers ◽

10.3390/cancers14020307 ◽

2022 ◽

Vol 14 (2) ◽

pp. 307

Author(s):

Martín Núñez Abad ◽

Silvia Calabuig-Fariñas ◽

Miriam Lobo de Mena ◽

Susana Torres-Martínez ◽

Clara García González ◽

...

Keyword(s):

Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Locally Advanced ◽

Malignant Neoplasm ◽

Predictive Biomarker ◽

Immune Checkpoints ◽

Hormone Receptor Positive

Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors.

Download Full-text

Elevated Level of Nerve Growth Factor (NGF) in Serum-Derived Exosomes Predicts Poor Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Cancers ◽

10.3390/cancers13215260 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5260

Author(s):

Hae Hyun Jung ◽

Ji-Yeon Kim ◽

Eun Yoon Cho ◽

Jung Min Oh ◽

Jeong Eon Lee ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Neoadjuvant Chemotherapy ◽

Medical Center ◽

Locally Advanced Breast Cancer ◽

Expression Patterns ◽

Univariate Analysis ◽

Locally Advanced ◽

Breast Cancer Patients ◽

Poor Survival

Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players in intercellular communication between tumors and their environments, and are involved in chemotherapy resistance. Recently, it was reported that cytokines can be packaged into exosomes, but whether exosomal cytokines serve as biomarkers in breast cancer patients is still unclear. In this study, we examined the roles of cytokines in both serum and exosomes as prognostic biomarkers for long-term outcomes in patients with breast cancer who undergo NAC. We isolated exosomes from the blood of 129 patients with early breast cancer who were receiving neoadjuvant chemotherapy between 2008 and 2011 at Samsung Medical Center. The levels of cytokines and growth factors in serum and exosomes were measured with ProcartaPlex immune-related panels. We investigated correlations between clinic-pathologic variables and patient survival, and Cox proportional hazards regression analysis was performed for prognostic evaluation. We detected significant differences in expression patterns between serum cytokines and exosomal cytokines. In both serum and exosomes, many cytokines were positively correlated with age. In univariate analysis, patients with high serum IP-10, serum MMP-1, and exosomal NGF had shorter overall survival. Exosomal NGF showed significantly poorer overall survival in multivariate analysis. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.

Download Full-text

Positive progress: current and evolving role of immune checkpoint inhibitors in metastatic triple-negative breast cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920909091 ◽

2020 ◽

Vol 12 ◽

pp. 175883592090909

Author(s):

Christine E. Simmons ◽

Christine Brezden-Masley ◽

Joy McCarthy ◽

Deanna McLeod ◽

Anil Abraham Joy

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Current Evidence ◽

First Line

Background: Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with historically poor overall outcomes, due primarily to a lack of effective targeted agents. Chemotherapy has been the primary treatment approach, although immune checkpoint inhibitors (ICIs) are currently being investigated to improve patient outcomes. This review examines the clinical implications of current evidence on the use of ICIs for the treatment of metastatic TNBC. Methods: Our systematic search identified two phase III and five phase I/II trials reporting on the efficacy of ICIs used as monotherapy or combined with chemotherapy for the treatment of metastatic TNBC. Results: The phase III IMpassion 130 trial showed a significant improvement in median progression-free survival in the intent-to-treat (net 1.7 months, p = 0.002) and PD-L1-positive populations (net 2.5 months, p < 0.001) for the addition of first-line atezolizumab versus placebo to nab-paclitaxel in metastatic TNBC. Although median overall survival was not significantly improved in patients receiving atezolizumab overall [net 2.3 months, hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.72–1.02, p = 0.078], numerical improvements in the PD-L1-positive population were compelling (net 7.0 months, HR 0.71; 95% CI 0.54–0.93). Toxicity profiles were as expected, and no new safety signals were observed. Pembrolizumab monotherapy did not significantly improve overall survival in similar patients that had received prior treatment in KEYNOTE-119. Conclusions: Atezolizumab plus nab-paclitaxel represents a potential new first-line standard of care for patients with metastatic PD-L1-positive TNBC. Other ICIs used as monotherapy, or combined with chemotherapy for advanced TNBC, as well as their use for earlier stage disease, are areas of ongoing investigation.

Download Full-text

CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer

Cancers ◽

10.3390/cancers13235878 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5878

Author(s):

Ilaria Magagna ◽

Nicolas Gourdin ◽

Yann Kieffer ◽

Monika Licaj ◽

Rana Mhaidly ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Breast Cancer Patients ◽

Large Collection ◽

Functional Assays ◽

Regulatory T Lymphocytes ◽

Potential Clinical Benefit ◽

Cd73 Expression

Background: Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance. Methods and Results: Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs. Conclusions: Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.

Download Full-text