scholarly journals A Genomic Approach to Integration of T Category and the Tumor Immune Microenvironment As Part of A Decision Algorithm for Radiation in Prostate Cancer

2020 ◽  
Vol 108 (3) ◽  
pp. e910
Author(s):  
N.K. Jairath ◽  
M. Farha ◽  
S. Srinivasan ◽  
C. Pesavento ◽  
C. Cheng
Keyword(s):  
Prostate Cancer ◽  
Immune Microenvironment ◽  
Decision Algorithm ◽  
Genomic Approach ◽  
Tumor Immune Microenvironment ◽  
T Category

scholarly journals Characterization of the m6A-Associated Tumor Immune Microenvironment in Prostate Cancer to Aid Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zezhen Liu ◽  
Jiehui Zhong ◽  
Jie Zeng ◽  
Xiaolu Duan ◽  
Jianming Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Poor Prognosis ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Intratumor Heterogeneity ◽  
Immune Microenvironment ◽  
Th2 Cell ◽  
Tumor Immune Microenvironment

The aim of this study was to elucidate the correlation between m6A modification and the tumor immune microenvironment (TIME) in prostate cancer (PCa) and to identify the m6A regulation patterns suitable for immune checkpoint inhibitors (ICIs) therapy. We evaluated the m6A regulation patterns of PCa based on 24 m6A regulators and correlated these modification patterns with TIME characteristics. Three distinct m6A regulation patterns were determined in PCa. The m6A regulators cluster with the best prognosis had significantly increased METTL14 and ZC3H13 expression and was characterized by low mutation rate, tumor heterogeneity, and neoantigens. The m6A regulators cluster with a poor prognosis had markedly high KIAA1429 and HNRNPA2B1 expression and was characterized by high intratumor heterogeneity and Th2 cell infiltration, while low Th17 cell infiltration and Macrophages M1/M2. The m6Ascore was constructed to quantify the m6A modification pattern of individual PCa patients based on m6A-associated genes. We found that the low-m6Ascore group with poor prognosis had a higher immunotherapeutic response rate than the high-m6Ascore group. The low-m6Ascore group was more likely to benefit from ICIs therapy. This study was determined that immunotherapy is more effective in low-m6Ascore PCa patients with poor prognosis.

scholarly journals 420 PROSTVAC in combination with nivolumab enhanced immune cell infiltration in prostate cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A450-A450
Author(s):  
Shania Bailey ◽  
Wiem Lassoued ◽  
Antonios Papanicolau-Sengos ◽  
Jennifer Marte ◽  
Nikki Williams ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Microenvironment ◽  
Invasive Margin ◽  
Control Tumor Growth ◽  
Tumor Immune Microenvironment ◽  
Control Tumor

BackgroundProstate cancer (PC) is the most common non-cutaneous diagnosed cancer among men in USA.1 Although clinical outcomes are favorable for patients with localized disease, 20–30% of patients will develop metastatic prostate cancer (mPC) and have poor prognosis. Immunotherapy, as a single agent, provides benefit to a small subset of PC patients, which is thought to be partially due to its known cold tumor immune microenvironment (TIME). Combination studies are needed to enhance benefit.2 Prostvac is a therapeutic cancer vaccine engineered to activate an immune response against prostate-specific Antigen (PSA).3 Prostvac alone could induce systemic immune response by increasing immune-cell infiltrates in and around the tumor.4 In this study, we are exploring the effect of Prostvac in combination with nivolumab in TIME in prostate cancer.MethodsWe treated locally advanced prostate cancer patients (n=6) undergoing radical prostatectomy (RP) with neoadjuvant Prostvac in combination with nivolumab, an immune checkpoint PD-1 inhibitor. Dynamic changes in TIME before and after treatment were studied using multiplex immunofluorescence (Opal Method). Formalin fixed paraffin-embedded sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with a validated T cell panel (DAPI, CD4, CD8, FOXP3, Ki67, Pan CK and PD-L1). To analyze the data, TIME was segmented into 3 compartments: intratumoral, invasive margin and benign.ResultsCombination immunotherapy significantly increased CD4+ T cell density in the invasive margin (mean 211.5 cells/mm2 vs 592.2 cells/mm2, p<0.05), with similar trend in the intratumoral and the benign compartments. CD8+ T cell density increased after treatment in the invasive margin (mean 47.25 cells/mm2 vs 157cells/mm2) and the benign compartment. 5/6 and 4/6 patients showed more than 2-fold increase of CD4 and CD8 T cells in the TIME, respectively, in at least one of the three compartments. Increased proliferative indices in CD4+ and CD8+ T cells were also seen after treatment. Tregs were present in low frequencies in TIME (maximum of 12 cells/mm2) with no significant changes. Moreover, a significant drop in tumor cell Ki67 after treatment (mean 252.8 cells/mm2 vs 100.5 cells/332, p<0.05) suggests that the combination may control tumor growth.ConclusionsThe combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patients. A broader examination of the TIME and the role immune cells undertake to control tumor growth is on-going.Trial RegistrationNCT02933255ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin (Internet) 2020;70:7–3Zhao SG, Lehrer J, Chang SL, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst 2018;111:301–10.Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vectorbased vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009;18:1001–11Abdul Sater H, Marté JL, Donahue RN, et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer 2020;8(1):655–64Ethics ApprovalThis study was performed in compliance with ethical standard and was approved by the NIH IRB, 17C-0007. All patients participating in this study gave an informed consent before taking part.

scholarly journals 668 A toolkit for the quantitative analysis of the spatial distribution of cells of the tumor immune microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A705-A705
Author(s):  
Anna Trigos ◽  
Tianpei Yang ◽  
Yuzhou Feng ◽  
Volkan Ozcoban ◽  
Maria Doyle ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Image Analysis ◽  
Spatial Distribution ◽  
Data Analysis ◽  
Spatial Data ◽  
R Package ◽  
Immune Microenvironment ◽  
Spatial Image ◽  
Tumor Immune Microenvironment ◽  
Cell Phenotypes

BackgroundSpatial technologies that query the location of cells in tissues such as multiplex immunohistochemistry and spatial transcriptomics are gaining popularity and are likely to become commonplace. The resulting data often includes the X, Y coordinates of millions of cells, cell phenotypes and marker or gene expression levels. In cancer, the spatial location of lymphocytes has been linked to prognosis and response to immunotherapy. While these advances have been exciting for the field, the methods currently being used are still coarse, making us severely underpowered in our ability to extract quantifiable information. Appropriate quantitative tools are desperately needed to refine and uncover novel biologically and clinically meaningful insights from the spatial distribution of cells of the tumor immune microenvironment.MethodsWe compiled over 60 prostate cancer and melanoma FFPE tumor sections and performed Opal multiplex immunohistochemistry for a diversity of T-cell and other immune markers, including CD3, CD4, CD8, FOXP3 and PDL1, as well as a prostate cancer (AMACR) or melanoma (SOX10) marker and DAPI. Following spectral imaging on the Vectra Polaris, we performed cell and tissue segmentation and phenotyping with the inForm or HALO image analysis software. The detected X, Y coordinates of cells and marker intensities were used for subsequent method development.ResultsWe developed SPIAT (Spatial Image Analysis of Tissues)1, an R package with a suite of data processing, quality control, visualization, data handling and data analysis tools for spatial data. SPIAT includes our novel algorithms for the identification of cell clusters, tumor margins and cell gradients, the calculation of neighborhood proportions and algorithms for the prediction of cell phenotypes. By interfacing with packages used in ecology, geographic data analysis and spatial statistics, we have begun to robustly address fundamental questions in the analysis of cell spatial data, such as metrics to measure mixing between cell types, the identification of tumor borders and statistical approaches to compare samples.ConclusionsSPIAT is compatible with multiplex immunohistochemistry, spatial transcriptomics and data generated from other spatial platforms, and continues to be actively developed. We expect SPIAT to become a user-friendly and speedy go-to package for the spatial analysis of cells in tissues, as well as promote the use of quantitative metrics in the spatial analysis of the tumor immune microenvironment.ReferencesTianpei Yang, Volkan Ozcoban, Anu Pasam, Nikolce Kocovski, Angela Pizzolla, Yu-Kuan Huang, Greg Bass, Simon P. Keam, Paul J. Neeson, Shahneen K. Sandhu, David L. Goode, Anna S. Trigos. SPIAT: An R package for the Spatial Image Analysis of Cells in Tissues. BioRxiv doi: https://doi.org/10.1101/2020.05.28.122614

scholarly journals A Novel Ferroptosis-Based Molecular Signature Associated with Biochemical Recurrence-Free Survival and Tumor Immune Microenvironment of Prostate Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhi-Bin Ke ◽  
Qi You ◽  
Jiang-Bo Sun ◽  
Jun-Ming Zhu ◽  
Xiao-Dong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Score ◽  
Biochemical Recurrence ◽  
Molecular Clusters ◽  
Molecular Signature ◽  
Recurrence Free Survival ◽  
Immune Microenvironment ◽  
Free Survival ◽  
Training Cohort ◽  
Tumor Immune Microenvironment

Objective: To identify ferroptosis-related molecular clusters, and to develop and validate a ferroptosis-based molecular signature for predicting biochemical recurrence-free survival (BCRFS) and tumor immune microenvironment of prostate cancer (PCa).Materials and Methods: The clinical data and transcriptome data of PCa were downloaded from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained from FerrDb database. We performed consensus clustering analysis to identify ferroptosis-related molecular subtypes for PCa. Univariate and multivariate Cox regression analysis were used to establish a ferroptosis-based signature for predicting BCRFS. Internal verification, external verification and subgroup survival analysis were then successfully performed.Results: There was a total of 40 differentially expressed FRGs in PCa. We then identified three ferroptosis-related molecular clusters of PCa, which have significantly different immune infiltrating cells, tumor immune microenvironment and PD-L1 expression level. More importantly, a novel ferroptosis-based signature for predicting BCRFS of PCa based on four FRGs (including ASNS, GPT2, NFE2L2, RRM2) was developed. Internal and external verifications were then successfully performed. Patients with high-risk score were associated with significant poor BCRFS compared with those with low-risk score in training cohort, testing cohort and validating cohort, respectively. The area under time-dependent Receiver Operating Characteristic (ROC) curve were 0.755, 0.705 and 0.726 in training cohort, testing cohort and validating cohort, respectively, indicating the great performance of this signature. Independent prognostic analysis indicated that this signature was an independent predictor for BCRFS of PCa. Subgroup analysis revealed that this signature was particularly suitable for younger or stage T III-IV or stage N0 or cluster 1-2 PCa patients. Patients with high-risk score have significantly different tumor immune microenvironment in comparison with those with low-risk score. The results of qRT-PCR successfully verified the mRNA expression levels of ASNS, GPT2, RRM2 and NFE2L2 in DU-145 and RWPE-1 cells while the results of IHC staining exactly verified the relative protein expression levels of ASNS, GPT2, RRM2 and NFE2L2 between PCa and BPH tissues.Conclusions: This study successfully identified three ferroptosis-related molecular clusters. Besides, we developed and validated a novel ferroptosis-based molecular signature, which performed well in predicting BCRFS and tumor immune microenvironment of PCa.

The tumor immune microenvironment differs between metastatic castrate resistant prostate cancer (CRPC) and hormone sensitive prostate cancer (HSPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 251-251 ◽  
Author(s):  
Kobe Chi Yung Yuen ◽  
Ben Tran ◽  
Peter Gibbs ◽  
Angelyn Anton ◽  
Sanjeev Mariathasan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoints ◽  
Cell Cycle Gene ◽  
Immune Microenvironment ◽  
Royal Melbourne Hospital ◽  
Molecular Subtyping ◽  
Molecular Features ◽  
Gene Sets ◽  
Tumor Immune Microenvironment ◽  
Castrate Resistant

251 Background: Immune checkpoint inhibitors (CPIs) (anti-CTLA4, anti-PD-1/PD-L1 mAbs) have had limited monotherapy activity in prostate cancer (PC) compared to urothelial cancer (UC). Recent biomarker studies revealed molecular features associated w/ better efficacy/resistance to CPIs in UC.1 Here we examined the tumor immune microenvironment (iTME) of hormone naïve/sensitive (HSPC) & castrate resistant prostate (CRPC) specimens from primary & metastatic sites, to determine if parallels to UC molecular correlates exist that will allow us to predict subsets of PC pts who are more likely to benefit from rational combination therapies w/ CPIs. Methods: Tumor FFPE archival tissues (HSPC, n = 98; CRPC, n = 46; Unk, n = 6) were sourced from a Royal Melbourne Hospital cohort of PC patients. Tissues were evaluated by H&E for TILs & IHC performed for PD-L1 (clones SP142 & SP263) & CD8. RNAseq was conducted & Lund bladder molecular subtyping performed during bioinformatics analyses. TCGA PRAD dataset was used for further validation. Results: We first applied Lund molecular subtyping to broadly categorize this cohort into luminal/basal subtypes. CRPC tumors were almost entirely luminal, whereas HSPC tumors were mainly basal. Luminal PC tumors enriched for Wnt gene sets (p = 0.026) & enriched for a genomically unstable (GU) subtype w/ higher expression of DNA damage repair (DDR) & cell cycle gene sets (p = 0.082). Compared to CRPC, HSPCs had higher numbers of infiltrating CD8s (p = 4.37e-004), increased expression of T-effector, MHC-I antigen presentation machinery, immune checkpoints, macrophages & activated stromal biology, including the fibroblast TGFβ response signature. PD-L1 on immune cells by SP142 & SP263 was 30% & 17% respectively & was enriched in HSPC samples (SP142: CRPC 18% vs. HSPC 34%, p = 0.08). Within patients w/ CRPC, differences were minimal between primary & metastatic samples. Conclusions: These analyses on the iTME contexture of PC reveal potentially actionable biological nodes for targeted therapies. These findings could inform future clinical strategies to improve CPI responses in CRPC & HSPC w/ rationale combinations.1. Mariathasan et al. Nature 2018.

Understanding the tumor-immune microenvironment in prostate cancer

2021 ◽  
Vol 33 (3) ◽  
pp. 231-237
Author(s):  
Liang Dong ◽  
Kayla V. Myers ◽  
Kenneth J. Pienta
Keyword(s):  
Prostate Cancer ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

scholarly journals Genome-Scale CRISPR-Cas9 Transcriptional Activation Screening in Metformin Resistance Related Gene of Prostate Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiahong Chen ◽  
Yaqiang Huang ◽  
Zhenfeng Tang ◽  
Maozhang Li ◽  
Xiaohui Ling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcriptional Activation ◽  
Immune Microenvironment ◽  
A Genome ◽  
Tumor Immune Microenvironment ◽  
Significant Gene ◽  
Diabetes Drug ◽  
High Level ◽  
Genome Scale

Metformin is a classic type II diabetes drug which possesses anti-tumor properties for various cancers. However, different cancers do not respond to metformin with the same effectiveness or acquire resistance. Thus, searching for vulnerabilities of metformin-resistant prostate cancer is a promising strategy to improve the therapeutic efficiency of the drug. A genome-scale CRISPR-Cas9 activation library search targeting 23,430 genes was conducted to identify the genes that confer resistance to metformin in prostate cancer cells. Candidate genes were selected by total reads of sgRNA and sgRNA diversity, and then a CCK8 assay was used to verify their resistance to metformin. Interestingly, we discovered that the activation of ECE1, ABCA12, BPY2, EEF1A1, RAD9A, and NIPSNAP1 contributed to in vitro resistance to metformin in DU145 and PC3 cell lines. Notably, a high level of RAD9A, with poor prognosis in PCa, was the most significant gene in the CCK8 assay. Furthermore, we discerned the tumor immune microenvironment with RAD9A expression by CIBERSORT. These results suggested that a high level of RAD9A may upregulate regulatory T cells to counterbalance metformin in the tumor immune microenvironment.

The tumor immune microenvironment of germline BRCA1/2 and sporadic prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 152-152
Author(s):  
Anna S. Trigos ◽  
Anupama Pasam ◽  
Patricia Diana Banks ◽  
Roslyn Wallace ◽  
Simon P. Keam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Dna Repair Genes ◽  
Cd4 Cells ◽  
Immune Microenvironment ◽  
Cd8 Cells ◽  
Tumor Immune Microenvironment ◽  
Repair Genes

152 Background: Prostate cancer (PC) is considered an immunologically ‘cold’ tumor and therefore patients are generally not considered good candidates for immunotherapy. Tumors arising in germline (g) BRCA1/2 mutation carriers are associated with higher genomic instability and levels of immune infiltration in breast and ovarian cancer. We investigated how germline mutations in DNA repair genes affect the tumor immune microenvironment (TME) of PC. Methods: Archival primary tumor samples from 26 patients with g BRCA2 mutations, 5 with g BRCA1, 5 with mutations in other DNA repair genes ( ATM, CHEK2, FANCI, PALB2 or BRCA2+ MSH2), and 26 sporadic patients were analyzed. OPAL multiplex immunohistochemistry was used to detect 7 markers (CD3, CD4, CD8, FOXP3, PDL1, AMACR, DAPI) to identify immune subsets and provide the X,Y coordinates of single cells. We developed novel computational distance-based methods to characterize the spatial distribution of cells. Gene expression was evaluated with the Nanostring panel of 770 immune genes. Results: g BRCA1/2 carriers showed lower levels of T cells (9.73% of the tumor stroma) compared to sporadic tumors (14.8%). In in both cothors the T cell population was dominated by CD4+ cells (69.5%), with CD8+ cells representing only 25.6%. Sporadic PCs displayed aggregation of T cells into large clusters in the stroma dominated by CD4+ cells and few CD8+ cells, while 77% of high-grade g BRCA2 patients were enriched in high levels of free, non-aggregated CD8+ T-cells in the tumor area. HLA-A expression was 2.37 times higher in g BRCA2 patients ( p = 3.4x10−8), who also showed higher expression of genes associated with a present but suppressed immune system ( p = 1.4x10−4). gBRCA2 patients with larger T-cell aggregates had an overall poorer prognosis compared to patients without (time to metastasis 55.1 vs. 85.3 months, survival time 67.3 vs. 85.0 months). Conclusions: g BRCA2 carriers displayed higher levels of HLA-A, more free CD8+ T cells infiltrating tumor regions and higher inflammatory signatures, suggesting an immune system that could potentially be harnessed. The degree of clustering of T cells (free vs. aggregated) within the TME may provide valuable prognostic information that warrants further validation.

NIR-active Nanoterminator with Mature Dendritic Cell Acitivities for Immuno-Priming Mild Photothermal Cancer Therapy

2020 ◽  
Author(s):  
zhihong sun ◽  
Guanjun Deng ◽  
Xinghua Peng ◽  
Xiuli Xu ◽  
Lanlan Liu ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Photothermal Therapy ◽  
Whole Body ◽  
Mature Dendritic Cell ◽  
Immune Microenvironment ◽  
Highly Efficient ◽  
Tumor Immune Microenvironment ◽  
Shock Proteins ◽  
Mild Temperature ◽  
Broad Interest

Recently, photothermal-immuno synergistic therapy under mild temperature (~ 45 °C) has got broad interest in cancer treatment. Inhibition the intratumorally HSPs production is the key to accomplish highly efficient and mild photothermal therapy. In this work, we developed biomimetic nanoterminators with mature DCs functions by coating the mature dendritic cell membrane on photothermal nanoagents. As-prepared nanoterminators could automatically locate on T cell in the complex tumor-immune microenvironment and promote the T cells proliferation, activation and cytokine secretion, which could not only inhibit the expression of heat shock proteins to cooperate on highly efficient mild photothermal therapy (~42°C), but also promote tumor apoptosis during the treatment. More importantly, this nanoterminator could serve as vaccine to trigger anti-tumor immune response of the whole body, which would be promising to long-life tumor inhibition and termination.

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