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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

ABSTRACT: Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

PROVIDER: PRJNA718568 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14108373.fastq.gz	Fastqsanger.gz
	SRR14108374.fastq.gz	Fastqsanger.gz
	SRR14108375.fastq.gz	Fastqsanger.gz
	SRR14108376.fastq.gz	Fastqsanger.gz
	SRR14108377.fastq.gz	Fastqsanger.gz

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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

Project description:One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine thatpotetiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I) that significantly promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex,as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigenprocessing activity of immunoproteasome, leading to enhanced major histocompatibility class I(MHC-I)-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation, empowers T-cell cytotoxicity, and thus elevates the tumorresponse to immunotherapy.

2021-03-31 | GSE171158 | GEO

Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.

Project description:One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.

| S-EPMC8121519 | biostudies-literature

Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

Project description:Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

| PRJNA398303 | ENA

Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Project description:Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

| S-EPMC5656607 | biostudies-literature

Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

Project description:Immune-checkpoint blockade (ICB) immunotherapy has emerged as one of the most effective therapies in oncology by unleashing anti-tumor response. However, despite the improvement in the clinical outcome of TNBC patients, most patients do not respond yet. Thus, to understand the underlying mechanisms of ICB resistance is necessary. With this purpose, we generated a preclinical immunocompetent syngeneic model of anti-PD-L1 ICB resistance. Mouse breast cancer 4TO7 cells were orthotopically implanted by MFP and at 0.5 x 0.5 cm tumor size mice were treated with anti-PD-L1 (10mg/Kg every 3 days). Though tumors initially responded, they eventually developed resistance to anti-PD-L1 treatment. Immunotherapy resistant tumor (IRT) cells and control tumor cells were isolated and validated again for anti-PDL1 resistance in vivo. RNA from isolated resistant tumor cells was obtained using Qiagen RNA extraction kit. Samples were analyzed by bioanalyzer. Poly-A sequencing was selected for library preparation, and samples were sequenced using Illumina Hi-Seq 2500 platform with 1x50 bp settings in the Centre of Genomic Regulation (CRG). Quality raw data was performed with FastQC software. Raw reads were then aligned with the STAR mapper to the Mus musculus genome and raw counts of reads per gene was additionally obtained with STAR. Differentially expression was assessed using DESeq2 version 1.30.1 package from R/Bioconductor. Among all the results, we have seen that those IRT cells have a downregulation of the antigen presentation machinery (APM) and an enrichment of stemness signatures. Overall, the results support the notion that ICB resistance emerge from low APM activity cell populations with associated stem cell-like phenotype.

2022-01-04 | GSE176580 | GEO

Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

Project description:Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

| PRJNA736735 | ENA

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Project description:Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is 1) strictly dependent on pyrimidine nucleotide depletion, 2) independent of canonical antigen presentation pathway transcriptional regulators, and 3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

| S-EPMC10103971 | biostudies-literature

Microbial mechanisms to improve immune checkpoint blockade responsiveness.

Project description:The human microbiota acts as a diverse source of molecular cues that influence the development and homeostasis of the immune system. Beyond endogenous roles in the human holobiont, host-microbial interactions also alter outcomes for immune-related diseases and treatment regimens. Over the past decade, sequencing analyses of cancer patients have revealed correlations between microbiota composition and the efficacy of cancer immunotherapies such as checkpoint inhibitors. However, very little is known about the exact mechanisms that link specific microbiota with patient responses, limiting our ability to exploit these microbial agents for improved oncology care. Here, we summarize current progress towards a molecular understanding of host-microbial interactions in the context of checkpoint inhibitor immunotherapies. By highlighting the successes of a limited number of studies focused on identifying specific, causal molecules, we underscore how the exploration of specific microbial features such as proteins, enzymes, and metabolites may translate into precise and actionable therapies for personalized patient care in the clinic.

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Oligomeric human Aβ1-42 inhibits antigen presentation

Project description:Oligomeric human Aβ1-42 inhibits antigen presentation

| PRJNA563674 | ENA

Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution [scRNA-seq]

Project description:We reported the CD8+ T cell exhaustion differences between chronic viral infection and tumor regarding their transcriptomic and epigenetic landscapes, immune checkpoint blockade responsiveness and underlying molecular mechanisms by using bulk RNA-seq, single-cell RNA-seq and single-cell ATAC-seq.

2022-11-29 | GSE152618 | GEO

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