scholarly journals High MMP-11 expression associated with low CD8+ T cells decreases the survival rate in patients with breast cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0252052
Author(s):  
Hyung Suk Kim ◽  
Min Gyu Kim ◽  
Kyueng-Whan Min ◽  
Un Suk Jung ◽  
Dong-Hoon Kim
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Survival Rate ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cell ◽  
Clinicopathological Parameters ◽  
Specific Gene ◽  
Gene Sets ◽  
Pathway Networks

Matrix metalloproteinase-11 (MMP-11) promote cancer invasion and metastasis through degrading the extracellular matrix. Protein degradation by MMP-11 in tumor cells may progressively suppress cancer surveillance activities with blocking immune response in breast cancer. The aim of study is to analyze clinicopathological parameters, molecular interactions and anticancer immune response in patients with MMP-11 expression and to provide candidate target drugs. We investigated the clinicopathologic parameters, specific gene sets, tumor antigenicity, and immunologic relevance according to MMP-11 expression in 226 and 776 breast cancer patients from the Hanyang University Guri Hospital (HUGH) cohort and The Cancer Genome Atlas (TCGA) data, respectively. We analyzed pathway networks and in vitro drug response. High MMP-11 expression was associated with worse survival rate in breast cancer from HUGH cohort and TCGA data (all p < 0.05). In analysis of immunologic gene sets, high MMP-11 expression was related to low immune response such as CD8+T cell, CD4+T cell and B cell. In silico cytometry, there was a decrease of cancer testis antigen and low tumor infiltrating lymphocyte in patient with high MMP-11 expression: activated dendritic cell, CD8+T cell, CD4+ memory T cell, and memory B cell. In pathway networks, MMP-11 was linked to the pathways including low immune response, response to growth hormone and catabolic process. We found that pictilisib and AZ960 effectively inhibited the breast cancer cell lines with high MMP-11 expression. Strategies making use of MMP-11-related hub genes could contribute to better clinical management/research for patients with breast cancer.

scholarly journals High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 1112
Author(s):  
Hyung Suk Kim ◽  
Byoung Kwan Son ◽  
Mi Jung Kwon ◽  
Dong-Hoon Kim ◽  
Kyueng-Whan Min
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Survival Rate ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Specific Gene ◽  
Breast Cancer Patients ◽  
Gene Sets

Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epigenetic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze survival, genetic interaction networks and anticancer immune responses in breast cancer patients with high KDM1A expression and to explore candidate target drugs. Methods: We investigated clinicopathologic parameters, specific gene sets, immunologic relevance, pathway-based networks and in vitro drug response according to KDM1A expression in 456 and 789 breast cancer patients from the Hanyang university Guri Hospital (HYGH) and The Cancer Genome Atlas, respectively. Results: High KDM1A expression was associated with a low survival rate in patients with breast cancer. In analyses of immunologic gene sets, high KDM1A expression correlated with low immune responses. In silico flow cytometry results revealed low abundances of CD8+T cells and high programmed death-ligand 1 (PD-L1) expression in those with high KDM1A expression. High KDM1A expression was associated with a decrease in the anticancer immune response in breast cancer. In pathway-based networks, KDM1A was linked directly to pathways related to the androgen receptor signaling pathway and indirectly to the immune pathway and cell cycle. We found that alisertib effectively inhibited breast cancer cell lines with high KDM1A expression. Conclusions: Strategies utilizing KDM1A may contribute to better clinical management/research for patients with breast cancer.

scholarly journals Application of HER2 peptide vaccines in patients with breast cancer: a systematic review and meta-analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zicong You ◽  
Weijun Zhou ◽  
Junyan Weng ◽  
Haizhan Feng ◽  
Peiqiao Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Survival Rate ◽  
T Cell ◽  
Clinical Studies ◽  
Cd8 T Cell ◽  
Delayed Type Hypersensitivity ◽  
Cochrane Library ◽  
Control Group ◽  
Cell Numbers ◽  
Before And After

Abstract Background The E75 and GP2 vaccines are the few therapeutic vaccines targeting HER2 currently under clinical research for patients with breast cancer. Methods Databases, including the Cochrane Library, PubMed, Medline, Embase, and Web of Science, were used to retrieve clinical studies on E75 and GP2 vaccines. Retrieval time was from the beginning of database construction until May 31st, 2021. Results A total of 24 clinical studies were included in this analysis, including 1704 patients in the vaccinated group and 1248 patients in the control group. For the E75 vaccine, there were significant differences between the vaccinated group and the control group in the delayed-type hypersensitivity reaction (SMD = 0.685 95% CI 0.52–0.85, PHeterogeneity = 0.186, PDTH < 0.05) and the change in CD8+ T-cell numbers (SMD = − 0.864, 95% CI − 1.02 to − 0.709, PHeterogeneity = 0.085, PCD8+ T cell < 0.05) before and after injection. For the GP2 vaccine, there was a significant difference between the vaccinated group and the control group in the change in CD8+ T-cell numbers (SMD = − 0.584, 95% CI − 0.803 to − 0.294, PHeterogeneity = 0.397, PCD8+ T cell < 0.05) before and after injection. In addition, the clinical outcomes, including recurrence rate (RR = 0.568, 95% CI 0.444–0.727, PHeterogeneity = 0.955, PRecurrence < 0.05) and disease-free survival rate (RR = 1.149, 95% CI 1.050–1.256, PHeterogeneity = 0.003, PDFS < 0.05), of the E75-vaccinated group were different from those of the control group. However, we found that the overall survival rate with the E75 vaccine (RR = 1.032, 95% CI 0.998–1.067, PHeterogeneity = 0.476, POS > 0.05) was not different between the two groups. Local and systemic toxicity assessments of the two vaccines showed minimal side effects. Conclusions The E75 vaccine was effective and safe in patients with breast cancer. The GP2 vaccine could elicit a strong immune response, but more trials are needed to confirm its clinical efficacy.

scholarly journals Human mena protein, a serex-defined antigen overexpressed in breast cancer eliciting both humoral and CD8+T-cell immune response

2004 ◽  
Vol 109 (6) ◽  
pp. 909-918 ◽  
Author(s):  
Francesca Di Modugno ◽  
Giovanna Bronzi ◽  
Matthew J. Scanlan ◽  
Duilia Del Bello ◽  
Simona Cascioli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cell ◽  
Protein A ◽  
Cd8 T Cell ◽  
Cell Immune Response

scholarly journals In Silico Modeling and Immunoinformatics Probing Disclose the Epitope Based PeptideVaccine Against Zika Virus Envelope Glycoprotein

2014 ◽  
Vol 2 (04) ◽  
pp. 44-57 ◽  
Author(s):  
Daga Dadjo Florian ◽  
Mohammad Mahfuz Ali Khan Shawan ◽  
Hafij Al Mahmud ◽  
Md. Mahmudul Hasan ◽  
Afroza Parvin ◽  
...  
Keyword(s):  
Amino Acids ◽  
Immune Response ◽  
T Cell ◽  
B Cell ◽  
Zika Virus ◽  
Envelope Glycoprotein ◽  
Peptide Vaccine ◽  
Cd8 T Cell ◽  
Peptide Sequence ◽  
Conformational Epitopes

Zika virus (ZIKV) is an aedes mosquito borne pathogen belonging to the member of flaviviridae subgroup is the causative agent of an emerging disease called Zika fever, known as a benign infection usually presenting as influenza like illness with cutaneous rash. Due to recent epidemic outbreaks it is realized as a major health risk which need enhanced surveillance, but no attempt has been made to design an epitope based peptide vaccine against Zika virus. Viral envelope proteins are derived from host cell membrane proteins with some viral glycoproteins and are used to cover their protective protein capsid, help the viruses to enter host cells and help them to avoid the host immune response. In this study, amino acid sequence of ZIKV envelope glycoprotein was obtained from a protein database and examined with in silico approaches to determine the most immunogenic epitopes for B cell and T cell which could induce humoral as well as cell mediated immune response. Both the linear and conformational epitopes for B cell were predicted by immunoinformatics tools housed in IEDB resources. The peptide sequence DAHAKRQTVVVLGSQEGAV from position 121 and peptide sequence from 117-137 amino acids were predicted as most potential B cell linear and conformational epitopes respectively. Epitopes for CD4+ and CD8+ T cell were also predicted by using tools within IEDB resource and peptide sequence MMLELDPPF from position 250-258 amino acids was predicted as most immunogenic CD8+ T cell epitope with immune response evoking ability prediction score (I pMHC) of 0.09139 and conservancy of 52.17%. The innate immune response for ZIKV envelope glycoprotein was determined by interferon (IFN)-gamma effectuation and mimicking capacity by immunoinformatics and molecular docking study respectively. However, this is an introductory approach to design an epitope based peptide vaccine against Zika virus; we hope this model will be very much helpful in designing and predicting novel vaccine candidate.

Transcriptional Hallmarks Of Tumor Infiltrating Lymphocyte Responses To Melanoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3491-3491 ◽  
Author(s):  
Natalie Collins ◽  
Jernej Godec ◽  
Lihua Zou ◽  
Martin C Mihm ◽  
Gad Getz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cd8 T Cell ◽  
Molecular Features ◽  
Immune Signatures ◽  
Gene Sets ◽  
Immune Response To Cancer

Abstract Tumor-infiltrating lymphocytes (TIL) are found in a subset of melanomas. Patients with pronounced TIL responses have an excellent prognosis, suggesting that for those patients, the infiltrating immune cells are part of an effective adaptive and/or innate response to cancer. However, the molecular features of brisk TIL infiltrates have not been analyzed in situ. Moreover, it is not clear whether the features of the immune response to melanoma are shared by other tumors. Here, we used histological grading of TIL infiltrates in melanoma samples from The Cancer Genome Atlas combined with analysis of immune signatures in transcriptional profiles from the same tumors to characterize the molecular features of the immune response to melanoma. To categorize the histological grade of immune infiltrate, we reviewed digital images of 156 melanoma samples, and assigned a TIL grade (0 - 3) based on established criteria. We found that the distribution of TIL grades in our dataset was consistent with previously published analyses. We first tested whether tumors with brisk infiltrate (TIL Grade 2 or 3) showed enrichment of immune signatures relative to those with non-brisk infiltrates (TIL Grade 0 or 1) using gene-set enrichment analysis (GSEA) with a collection of ∼2000 immune-related gene-sets manually curated from published studies of adaptive and innate immunity. We found that 493 immune signatures enriched in brisk tumors (FDR<0.25), while none enriched in non-brisk tumors, suggesting that the histological TIL grade was strongly associated with transcriptional features of an immune response. Gene-sets that enriched in tumors with brisk infiltrates included those derived from CD4 and CD8 T cells (evidenced by increased expression of T cell lineage-specific genes such as CD3G, ZAP70, CD28, TBX21, PRDM1, GZMB, PRF1); those related to monocytes (CD14); as well as Type I interferon response genes (OAS1, IFI44). Surprisingly we did not find enrichment of gene-sets related to CD8 T cell exhaustion. Instead, we found highly significant enrichment of effector CD8 T cell gene-sets that featured effector cytokines, such as IFNG and TNF, and cytokine receptors such as IL-15R and IL-2RB, genes that which are normally decreased in expression in exhausted T cells. This suggests that the transcriptional profile of brisk immune infiltrates in melanoma includes features of highly functional CD8 effector T cell responses and lacks transcriptional features of exhaustion. We next tested whether the signatures of immune response to melanoma were enriched in other tumors. We identified a core set of “TIL hallmark genes” comprised of GSEA leading-edge genes from multiple gene-sets enriched in brisk vs. non-brisk melanoma samples. We then grouped the gene expression profiles of other tumor histologies according to their expression of TIL hallmark genes using single-sample GSEA. In thyroid cancer, for example, we found that the enrichment of melanoma TIL hallmark genes was strongly correlated with the presence of lymphocyte infiltrates, suggesting that there are common features of the immune response to cancer in different tumor types. Our results show that integrated analysis of histology and gene expression profiles from melanoma samples can identify the molecular features of the TIL response. We find evidence for signatures of effective CD8 T cell responses in brisk infiltrate melanomas that are shared by other tumor types. These TIL hallmark genes may help identify molecular subsets of immunogenic tumors, providing novel outcome predictors, and opportunities to stratify immunotherapeutic treatment options. More broadly, this approach can help deconvolve tumor/host gene expression profiles and better characterize the human immune response to cancer. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Accelerated Progression of Disseminated Coccidioidomycosis Following SARS-CoV-2 Infection: A Case Report

2021 ◽  
Author(s):  
Daniel S Krauth ◽  
Christina M Jamros ◽  
Shayna C Rivard ◽  
Niels H Olson ◽  
Ryan C Maves
Keyword(s):  
Immune Response ◽  
Case Report ◽  
T Cell ◽  
Cellular Response ◽  
Cd8 T Cell ◽  
Host Immune Response ◽  
Cell Senescence ◽  
Functional Exhaustion ◽  
T Cell Senescence

ABSTRACT We describe a patient with subclinical coccidioidomycosis who experienced rapid disease dissemination shortly after SARS-CoV-2 infection, suggesting host immune response dysregulation to coccidioidomycosis by SARS-CoV-2. We hypothesize that disrupted cell-mediated signaling may result after SARS-CoV-2 infection leading to functional exhaustion and CD8+ T-cell senescence with impairment in host cellular response to Coccidioides infection.

scholarly journals Nano-Microparticle Platforms in Developing Next-Generation Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 606
Author(s):  
Giuseppe Cappellano ◽  
Hugo Abreu ◽  
Chiara Casale ◽  
Umberto Dianzani ◽  
Annalisa Chiocchetti
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Humoral Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Next Generation ◽  
Emerging Viruses ◽  
Whole Cells ◽  
Effector Functions

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

scholarly journals 614 Investigating immune mediated mechanisms of PARPi resistance in BRCA1-associated triple negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
Anita Mehta ◽  
Madeline Townsend ◽  
Madisson Oliwa ◽  
Patrice Lee ◽  
Nicholas Saccomano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Triple Combination ◽  
Tumor Clearance ◽  
Sting Pathway

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi) have improved the outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. Our preclinical studies demonstrated that PARPi activates the cGAS/STING pathway and recruitment of anti-tumor CD8+ T-cells that are required for tumor clearance [1]. These studies contributed to development of clinical trials testing PARPi plus immune checkpoint blockade (ICB). Unfortunately, early phase trials of PARPi + ICB have not yet suggested efficacy will be superior to PARPi monotherapy. Lack of demonstrated clinical synergy between PARPi + ICB underscores the need to study the tumor microenvironment (TME) during PARPi therapy to identify optimal strategies to enhance T-cell activation. We recently showed that PARPi induces CSF-1R+ suppressive tumor associated macrophages (TAMs) that restrict antitumor immune responses, contributing to PARPi resistance [2]. Removing TAMs with anti-CSF-1R therapy in combination with PARPi significantly enhanced overall survival (OS) compared to PARPi monotherapy in preclinical models [2]. Here, we investigate how modulating TAMs can enhance PARPi + ICB.MethodsMice bearing BRCA1-deficient TNBC (K14-Cre;Brca1f/f;p53f/f) tumors were treated for 98 days with PARPi (Talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and then followed for survival. Flow cytometry was employed to elucidate changes in the TME after treatment.ResultsPARPi conferred a significant survival advantage over vehicle treated mice (median OS 33 v. 14 days; p=0.0034) and 2/8 PARPi-treated mice experienced complete tumor clearance at day 98. PARPi + CSF-1Ri treated mice (median OS 140 days) remarkably cleared 7/10 tumors by day 98. The addition of anti-PD-1 to PARPi did not enhance OS compared to PARPi monotherapy. The triple combination of anti-PD-1 + PARPi + CSF-1Ri has not yet significantly enhanced the median OS compared to PARPi + CSF-1Ri (ongoing; 168 v. 140 days); nor did it increase clearance of tumor by day 98 (7/10). However, the triple combination led to superior long term tumor clearance. At day 161 the triple combination exhibited 5/10 tumor free mice compared to 2/10 treated with PARPi + CSF-1Ri. To elucidate how CSR-1Ri enhanced PARPi + ICB responses, flow cytometry was performed and revealed increased expression of the co-stimulatory molecule CD80, reduced tissue resident macrophages (CX3CR1+) and lower CSF-1R expression compared to PARPi + ICB.ConclusionsThese data suggest that targeting immunosuppressive macrophages may induce a favorable anti-tumor immune response and enhance responses to PARPi plus ICB. We are currently evaluating the adaptive immune response in this context.ReferencesPantelidou, C., et al., PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discovery, 2019: p. CD-18-1218.Mehta, A.K., et al., Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2021. 2(1): p. 66–82.

scholarly journals Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine

2021 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Sloan A. Lewis ◽  
Brianna Doratt ◽  
Allen Jankeel ◽  
Izabela Ibraim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Natural Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses

mRNA based vaccines for SARS-CoV-2 have shown exceptional clinical efficacy providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4 T cells, and robust antigen-specific polyfunctional CD4 T cell responses in all vaccinees. On the other hand, CD8 T cell responses were both weak and variable. Interestingly, clonally expanded CD8 T cells were observed in every vaccinee, as observed following natural infection. TCR gene usage, however, was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response where early CD4 T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8 T cells, together capable of contributing to future recall responses.

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