scholarly journals TP53 Mutation Infers a Poor Prognosis and Is Correlated to Immunocytes Infiltration in Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Ziwen Zhang ◽  
Ran Hao ◽  
Qiusheng Guo ◽  
Sheyu Zhang ◽  
Xiaojia Wang
Keyword(s):  
Breast Cancer ◽  
Antigen Processing ◽  
Tp53 Mutation ◽  
Immune Therapy ◽  
Therapy Response ◽  
Independent Predictive Factor ◽  
Mutation Burden ◽  
In The Wild ◽  
Genome Consortium ◽  
Antigen Processing And Presentation

Background: This study aimed to investigate the TP53 mutation, its potential immune features, its prognostic value, and its impact on immune infiltration in patients with breast cancer (BC).Methods: We downloaded the somatic mutation data and clinicopathologic features of BC patients from the TCGA GDC database, UCSC Xena platform, and International Cancer Genome Consortium (ICGC) database. The association between the TP53 mutation, clinicopathology features, and overall survival (OS) in BC patients was analyzed. We evaluated the potential role of the TP53 mutation in the immune therapy response, including the tumor mutation burden (TMB), microsatellite instability (MSI), and tumor immune dysfunction and exclusion (TIDE). Moreover, ESTIMATE was employed to assess the ImmuneScore and StromalScore in BC patients. We also explored immunocyte infiltration related to the TP53 mutation and its potential mechanism. Immunohistochemistry (IHC) was performed to validate the association between the expression of CXCL1, CXCL10, and CCL20 and TP53 status.Results: We found that the TP53 mutation was significantly associated with the shorter OS (p = 0.038) and was also an independent predictive factor of OS for BC patients (p < 0.001). Compared to that in the wild type group, the TP53-mutant group showed a higher TMB value (P< 0.001), MSI value (p = 0.077), and TIDE value (p < 0.001) with respect to BC patient immunotherapy. In addition, the ImmuneScore and StromalScore were both significantly increased in the TP53-mutant group (ImmuneScore: p < 0.001; StromalScore: p = 0.003). The results of CIBERSORT suggested that the TP53 mutation significantly promoted the infiltration of Tregs, T helper cells, and M0-type macrophages. KEGG and GSEA enrichment results suggested that the IL-17 signaling pathway and antigen processing and presentation pathways were significantly enriched in the TP53-mutant group. Importantly, based on IHC results of immune-related hub-genes, the chemokines CXCL1, CXCL10, and CCL20 were significantly upregulated in the TP53-mutant group in BC patients.Conclusion: These results indicate that a TP53 mutation might serve as a biomarker for BC prognosis and is related to immunocyte infiltration in the tumor microenvironment.

scholarly journals Development of a Novel Prognostic Signature Based on Antigen Processing and Presentation in Patients with Breast Cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Aoshuang Qi ◽  
Mingyi Ju ◽  
Yinfeng Liu ◽  
Jia Bi ◽  
Qian Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antigen Processing ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
Gene Set ◽  
Antigen Processing And Presentation

Background: Complex antigen processing and presentation processes are involved in the development and progression of breast cancer (BC). A single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer; however, there have been few attempts to find a robust antigen processing and presentation-related signature to predict the survival outcome of BC patients with respect to tumor immunology. Therefore, we aimed to develop an accurate gene signature based on immune-related genes for prognosis prediction of BC.Methods: Information on BC patients was obtained from The Cancer Genome Atlas. Gene set enrichment analysis was used to confirm the gene set related to antigen processing and presentation that contributed to BC. Cox proportional regression, multivariate Cox regression, and stratified analysis were used to identify the prognostic power of the gene signature. Differentially expressed mRNAs between high- and low-risk groups were determined by KEGG analysis.Results: A three-gene signature comprising HSPA5 (heat shock protein family A member 5), PSME2 (proteasome activator subunit 2), and HLA-F (major histocompatibility complex, class I, F) was significantly associated with OS. HSPA5 and PSME2 were protective (hazard ratio (HR) < 1), and HLA-F was risky (HR > 1). Risk score, estrogen receptor (ER), progesterone receptor (PR) and PD-L1 were independent prognostic indicators. KIT and ACACB may have important roles in the mechanism by which the gene signature regulates prognosis of BC.Conclusion: The proposed three-gene signature is a promising biomarker for estimating survival outcomes in BC patients.

scholarly journals If we build it they will come: targeting the immune response to breast cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Margaret E. Gatti-Mays ◽  
Justin M. Balko ◽  
Sofia R. Gameiro ◽  
Harry D. Bear ◽  
Sangeetha Prabhakaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antigen Processing ◽  
Antitumor Immunity ◽  
Objective Response ◽  
Suppressor Cells ◽  
Effector T Cells ◽  
Therapeutic Modalities ◽  
Mutational Burden ◽  
Antigen Processing And Presentation ◽  
Shed Light

Abstract Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance.

scholarly journals Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1674
Author(s):  
Sara Tomei ◽  
Ola Ibnaof ◽  
Shilpa Ravindran ◽  
Soldano Ferrone ◽  
Cristina Maccalli
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Immune Responses ◽  
Antigen Processing ◽  
Aberrant Expression ◽  
Immunological Profile ◽  
Malignant Lesions ◽  
Novel Therapeutic Strategies ◽  
Antigen Processing And Presentation

Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.

scholarly journals Epigenetic mechanisms in breast cancer therapy and resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liliana Garcia-Martinez ◽  
Yusheng Zhang ◽  
Yuichiro Nakata ◽  
Ho Lam Chan ◽  
Lluis Morey
Keyword(s):  
Breast Cancer ◽  
Therapy Response ◽  
Disease Recurrence ◽  
Therapeutic Resistance ◽  
Breast Cancers ◽  
Epigenetic Factors ◽  
Breast Cancer Therapy ◽  
Resistant Phenotype ◽  
Early Adoption ◽  
Clinical Resistance

AbstractThe majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent the main treatment modality. Endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse. Recent studies increased our understanding in how changes to the chromatin landscape and deregulation of epigenetic factors orchestrate the resistant phenotype. Here, we will discuss how the epigenome is an integral determinant in hormone therapy response and why epigenetic factors are promising targets for overcoming clinical resistance.

scholarly journals Metastasis is altered through multiple processes regulated by the E2F1 transcription factor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthew R. Swiatnicki ◽  
Eran R. Andrechek
Keyword(s):  
Breast Cancer ◽  
Transgenic Mouse Models ◽  
Cellular Processes ◽  
Mouse Tumors ◽  
Mutation Burden ◽  
Multiple Processes ◽  
Metastatic Process ◽  
Cycle Regulation ◽  
Bioinformatic Approach ◽  
Complicated Nature

AbstractThe E2F family of transcription factors is important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis and metastasis. Alteration of the Rb/E2F pathway occurs in various forms of cancer, including breast cancer. E2F1 ablation has been shown to decrease metastasis in MMTV-Neu and MMTV-PyMT transgenic mouse models of breast cancer. Here we take a bioinformatic approach to determine the E2F1 regulated genomic alterations involved in the metastatic cascade, in both Neu and PyMT models. Through gene expression analysis, we reveal few transcriptome changes in non-metastatic E2F1−/− tumors relative to transgenic tumor controls. However investigation of these models through whole genome sequencing found numerous differences between the models, including differences in the proposed tumor etiology between E2F1−/− and E2F1+/+ tumors induced by Neu or PyMT. For example, loss of E2F1 within the Neu model led to an increased contribution of the inefficient double stranded break repair signature to the proposed etiology of the tumors. While the SNV mutation burden was higher in PyMT mouse tumors than Neu mouse tumors, there was no statistically significant differences between E2F WT and E2F1 KO mice. Investigating mutated genes through gene set analysis also found a significant number of genes mutated in the cell adhesion pathway in E2F1−/− tumors, indicating this may be a route for disruption of metastasis in E2F1−/− tumors. Overall, these findings illustrate the complicated nature of uncovering drivers of the metastatic process.

scholarly journals Cysteine Cathepsins and Their Prognostic and Therapeutic Relevance in Leukemia

2021 ◽  
Author(s):  
Mohit Arora ◽  
Garima Pandey ◽  
Shyam S. Chauhan
Keyword(s):  
Antigen Processing ◽  
Hematological Malignancies ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Cysteine Cathepsins ◽  
Expression Activity ◽  
Available Information ◽  
Antigen Processing And Presentation ◽  
Selection Of

AbstractCysteine cathepsins are lysosomal proteases that require Cys-His ion pair in their catalytic site for enzymatic activity. While their aberrant expression and oncogenic functions have been widely reported in solid tumors, recent findings suggest that these proteases also play an important role in the pathogenesis of hematological malignancies. In this review, we summarize the potential clinical implications of cysteine cathepsins as diagnostic and prognostic markers in leukemia, and present evidences which supports the utility of these proteases as potential therapeutic targets in hematological malignancies. We also highlight the available information on the expression patterns, regulation, and potential functions of cysteine cathepsins in normal hematopoiesis and hematological malignancies. In hematopoiesis, cysteine cathepsins play a variety of physiological roles including regulation of hematopoietic stem cell adhesion in the bone marrow, trafficking, and maturation. They are also involved in several functions of immune cells which include the selection of lymphocytes in the thymus, antigen processing, and presentation. However, the expression of cysteine cathepsins is dysregulated in hematological malignancies where they have been shown to play diverse functions. Interestingly, several pieces of evidence over the past few years have demonstrated overexpression of cathepsins in leukemia and their association with worst survival outcomes in patients. Strategies aimed at altering the expression, activity, and subcellular localization of these cathepsins are emerging as potential therapeutic modalaties in the management of hematological malignancies. Recent findings also suggest the involvement of these proteases in modulating the immune response in leukemia and lymphomas.

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