Signature of immunotherapy-responsive prostate cancer
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ABSTRACT:
PROVIDER: PRJEB34378 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint blockade (ICB) therapy intends to only benefit a fraction of cancer patients, and combination immunotherapy with a compound is a promising treatment to overcome this limitation. Here, a tumor immunological phenotype (TIP) gene signature and high throughput sequencing-based high throughput screening (HTS2) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature, which expression pattern distinguishes “cold” tumors from “hot” tumors, and predicts ICB response in cancer patients. Then, after screening thousands of compounds, we identified that aurora kinase inhibitors, including ENMD-2076 and TAK-901, could reprogram the expression pattern of TIP genes from “cold” tumor to “hot” tumor in triple negative breast cancer (TNBC) cells. The treatment of aurora kinase inhibitors on TNBC cells dramatically up-regulates expression of Th1 type chemokine genes CXCL10 and CXCL11, which promotes effective T cells infiltrating into tumor microenvironment and significantly improves anti-PD-1 efficacy in inhibiting the tumor growth of TNBC in preclinical models. Mechanistically, these aurora kinase inhibitors are mainly through inhibiting AURKA-STAT3 signaling pathway to stimulate the expression of CXCL10 and CXCL11. Our study established a high throughput strategy to discover candidate compounds for combination immunotherapy, and suggested the therapeutic potential of combining aurora kinase inhibitors with checkpoint blockade immunotherapy for the treatment of TNBC.
2020-12-31 | GSE160071 | GEO
Project description:<p>We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway and re-expression of epigenetically silenced endogenous retrovirus. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.</p>
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Project description:Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Targeted sequencing of tissue-extracted DNA and RNA was performed using the Oncomine Immune Response Research Assay to evaluate 395 genes involved in the immune response and calculate the tumor mutation burden. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers (PD-L1, tumor infiltrating lymphocytes, tumor mutation burden). M1 and peripheral T cell signature of tumors may enable prediction of durable response and maximize the benefit of ICIs in patients with NSCLC.
2020-02-03 | GSE136961 | GEO
Project description:Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs), partly because there are immunosuppressive myeloid cells in tumours. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1hi-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8+ T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1hi-TAM-mediated immunosuppression in CD8+ T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.
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Project description:Immune checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) is effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable response. Therefore, predictive biomarkers of clinical response are urgently needed. Here, we employed high-dimensional single cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of metastatic melanoma patients before and after anti-PD-1 immunotherapy. During therapy, we observed a clear treatment response to immunotherapy in the T cell compartment. However, prior to commending therapy a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. In order to determine whether there are cell intrinsic changes in the monocyte signature, we performed RNA sequencing on sorted CD14+CD16-HLA-DRhi cells from HD, NR and R at baseline. Representative samples (n=4, each) of responders/non responders/ and healthy donors were selected from archival samples stored in the dermatology biobank according to the same clinical criteria used in the discovery and validation cohorts for CyTOF and FACS analysis. CD14+CD16-HLA-DRhiLin- (CD3, CD4, CD19, CD45RO) monocytes were sorted from frozen PBMC form blood samples from HD, R and NR at baseline.
2017-12-20 | E-MTAB-6214 | biostudies-arrayexpress
Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells. Transcriptional analysis of 10 uncultured prostatic basal and luminal populations from either the benign or malignant prostate tissue of 8 human prostate cancer patients by high-throughput RNA-seq
2016-06-01 | E-GEOD-82071 | biostudies-arrayexpress
Project description:In recurrent/metastatic (RM) head and neck squamous cell cancer (HNSCC) not amenable to salvage surgery or radiation, the overall survival remains unsatisfactory, and the patients often experience a huge burden of symptoms requiring treatments that could achieve objective response on the disease itself. Recently, treatment with immune checkpoint inhibitors (ICI) has shown survival benefit in randomized clinical trials both in the setting of platinum pre-treated patients and in patients at their first line of treatment, with the expression of PDL1 on the tumor. Despite the introduction of ICI, only a small subset of RM HNSCC patients achieves long-term survivorship. We aim at identifying predictors of outcome and evaluating a gene expression signature (Cl6-immunereactive) in patients treated with ICI therapy. Our data highlight the presence of biological underlying differences able to predict outcome following treatment with ICI for platinum-refractory RM-HNSCC.
2023-12-31 | GSE212550 | GEO
Project description:In recurrent/metastatic (RM) head and neck squamous cell cancer (HNSCC) not amenable to salvage surgery or radiation, the overall survival remains unsatisfactory, and the patients often experience a huge burden of symptoms requiring treatments that could achieve objective response on the disease itself. Recently, treatment with immune checkpoint inhibitors (ICI) has shown survival benefit in randomized clinical trials both in the setting of platinum pre-treated patients and in patients at their first line of treatment, with the expression of PDL1 on the tumor. Despite the introduction of ICI, only a small subset of RM HNSCC patients achieves long-term survivorship. We aim at identifying predictors of outcome and evaluating a gene expression signature (Cl6-immunereactive) in patients treated with ICI therapy. Our data highlight the presence of biological underlying differences able to predict outcome following treatment with ICI for platinum-refractory RM-HNSCC.
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Project description:Building on the observation that metastatic, castration-resistant prostate cancer (CRPC) correlates with activation of Src-family tyrosine kinases, we showed that the expression of activated Src renders LNCaP androgen-independent. Here, we report on RNA-seq and/or AR ChIP-seq analyses of LNCaP, LNCaP[Src], VCaP, 22Rv1 cells grown in the presence or absence of 10 nM DHT for 16h, or LuCaP35.1 tumors grown in androgen-supplemented vs. castrated mice (androgen-dependent vs. castration-resistant). We identify an 11-gene Src-induced signature found only in CRPC in response to DHT, and moreover, the differentail expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival.
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