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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [RNA-seq]

ABSTRACT: BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [RNA-seq]

PROVIDER: PRJNA820045 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18489904_1.fastq.gz	Fastqsanger.gz
	SRR18489904_2.fastq.gz	Fastqsanger.gz
	SRR18489827_1.fastq.gz	Fastqsanger.gz
	SRR18489827_2.fastq.gz	Fastqsanger.gz
	SRR18489828_1.fastq.gz	Fastqsanger.gz

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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

Project description:BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [NanoString_IMM]

Project description:BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [NanoString_IMM]

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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [NanoString_IMM]

Project description:Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice to stratify future urothelial cancer patient treatment strategies.

2022-05-05 | GSE199616 | GEO

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [NanoString IO360]

2022-05-05 | GSE199617 | GEO

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [NanoString IO360]

Project description:BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [NanoString IO360]

| PRJNA820856 | ENA

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [RNA-seq]

Project description:Patients with high-risk non-muscle-invasive bladder carcinoma (NMIBC) frequently relapse after standard BCG immunotherapy and have a dismal outcome after progression to muscle-invasive bladder carcinoma (MIBC). Although BCG induces potent inflammatory responses upon intravesical instillations, the mechanisms of tumor resistance to such immunotherapy remain elusive. We performed a longitudinal immune profiling of a cohort of MIBC pre- and post BCG therapy with gene and protein expression analysis to establish correlations with 5 year clinical follow up. Here, we demonstrate two distinct patterns of BCG-induced immunosubversion, which include acquired immune resistance and tumor-cell intrinsic resistance. Firstly, intracellular BCG infection of a subset of urothelial carcinoma cells downregulated HLA-I expression and induced epithelial to mesenchymal transition (EMT) characteristics. BCG treated tumors exhibiting such HLA class I loss displayed an immune desert tumor microenvironment dominated by myeloid immunosuppressive cells. Such patients presented with early cancer relapses and a bad outcome. Conversely, BCG-treated tumors which did not lose HLA class I antigens at relapse displayed an immune escape mechanism dominated by a Th1 pattern with high expression of inhibitory checkpoints and exhaustion markers. Such patients had a favorable outcome upon second surgery. We surmise that HLA class I expression does not result from immunoediting but rather from an EMT process associated to myeloid immunosuppression that predicts dismal prognosis.

2022-05-05 | GSE199471 | GEO

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer.

Project description:Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I-deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I-proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint-inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer.

| S-EPMC9197524 | biostudies-literature

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) reprograms melanoma microenvironment to promote antitumor T cell responses

Project description:Intralesional therapy using Mycobacterium bovis Bacillus Calmette-Guérin (BCG) for cutaneous metastatic melanoma induces regression of injected, but also non-injected lesions. Tumor-associated macrophages (also known as M2) infiltrate solid tumors and impair antitumor immunity. Since macrophages play a pivotal role in both tumors and mycobacterial infections, we hypothesized BCG alters M2 to promote antitumor immunity. BCG-treated, in vitro-polarized M2 (M2-BCG) show dramatic transcriptional changes involving inflammation, immune cell recruitment, cross-talk and activation pathways. Mechanistic network analysis indicates potential for M2-BCG to improve IFN-γ responses, frequently used as a marker for successful antitumor immunity. Accordingly, we found an increased frequency of IFN-γ-producing CD4+ T cells responding to M2-BCG vs mock-treated M2 (p<0.05). Moreover, supernatant from M2-BCG increased the frequency of granzyme B-producing CD8+ tumor-infiltrating lymphocytes (TIL) responding to autologous melanoma cell lines (p<0.01). Comparing the transcriptome of injected vs uninjected lesions biopsied from IL-BCG patients showed immune function prevailing in injected lesions, with the most enriched pathways representing T cell activation mechanisms. In vitro BCG-infected tumor cells also stimulated IFN-γ production from HLA-A2-restricted syngeneic TIL from the same melanoma patient (p<0.05). Together, our data indicates BCG can promote an antitumor microenvironment in cutaneous metastatic melanoma.

2017-09-14 | GSE90748 | GEO

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-05-05 | GSE199618 | GEO

HLA-B35 upregulates ET-1 and downregulates eNOS via ER stresss response in endothelial cells

Project description:The presence of the HLA-B35 allele has emerged as an important risk factor for the development of isolated pulmonary hypertension (iPHT) in patients with Scleroderma (SSc), however the mechanisms underlying this association have not been fully elucidated. The goal of our study was to determine the molecular mechanisms that mediate the biological effects of HLA-B35 in endothelial cells (ECs). Our data demonstrate that HLA-B35 expression at the physiological levels using via adenoviral vector resulted in a significantly increased endothelin-1 (ET-1) and a significantly decreased endothelial nitric oxide synthase (eNOS) mRNA and protein levels. Furthermore, HLA-B35 greatly upregulated expression of cytoplasmic chaperones, including heat shock proteins (HSPs) HSP70 (HSPA1A and HSPA1B) and HSP40 (DNAJB1 and DNAJB9), suggesting that HLA-B35 induced the ER stress and unfolded protein response (UPR) in ECs. Examination of selected mediators of the UPR response, including BiP (GRP78), CHOP (GADD153), ERO1 (endoplasmic reticulum oxidase) and PDI (protein disulfide isomerase) has revealed a consistent increase of BiP expression levels. Accordingly, Thapsigargin (TG), a known ER stress inducer, stimulated ET-1 mRNA and protein levels in ECs. This study suggests that HLA-B35 could contribute to endothelial cell dysfunction via ER stress mediated induction of ET-1 in patients with PHT.

2010-03-01 | GSE20055 | GEO

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