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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: Not available

| 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

Targeting PAR2 reprograms myeloid cells to enhance antigen presentation and potentiate PD-1 checkpoint blockade therapy

Project description:Identifying the mechanisms underlying resistance to immune checkpoint inhibitors (ICIs) has become a major focus in cancer immunotherapy. Our previous work identified F2RL1 expression, encoding the G protein-coupled receptor Protease-Activated Receptor-2 (PAR-2), as a negative biomarker of ICIs responsiveness. In this study, we evaluated the potential of targeting PAR-2 to enhance the efficacy of anti-PD-1 treatment. Using a sensitive protein-based assay, we observed that activated PAR-2 levels were significantly elevated in the serum samples of cancer patients across multiple tumor types and correlated with reduced survival of lung cancer patients treated with pembrolizumab plus platinum-based chemotherapy. Global F2rl1 gene deletion in mice, as well as pharmacological inhibition of PAR-2 with a potent, selective and insurmountable negative allosteric modulator, I-117, significantly potentiated anti-PD-1 therapy in preclinical studies. Mechanistically, PAR-2 inhibition reshaped the tumor immune microenvironment, notably by reducing the frequency of putative immunosuppressive myeloid cells and increasing the activation of CD8⁺ T cells in tumors and tumor-draining lymph nodes (tDLNs). These cellular changes were accompanied by a shift in the cytokine milieu favoring T helper 1 (Th1)-type cytokines and decreasing immunosuppressive cytokines. Notably, bulk RNA sequencing of myeloid cells suggested that PAR-2 activity prevented effective antigen presentation. Accordingly, using ex vivo co-culture assays, we demonstrated that the antigen-presenting functions of tumor-associated and draining lymph node CD11c+ dendritic cells were significantly enhanced when mice were treated with the PAR-2 inhibitor I-117.These findings support a model where PAR‑2 inhibition primes tumor antigen presentation and enhances PD‑1 blockade, providing rationale for their combined use in cancer immunotherapy.

2026-08-26 | GSE306584 | GEO

Ferroptotic tumor cells revamp tumor-associated macrophage antigen presentation to unleash immune checkpoint blockade efficacy

Project description:Ferroptotic tumor cells revamp tumor-associated macrophage antigen presentation to unleash immune checkpoint blockade efficacy

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DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation

Project description:Innate immune receptors often induce activation of conventional dendritic cells (cDCs) and enhance antigen (cross-)presentation, favouring immune responses. DNGR-1 (CLEC9A), a receptor expressed by type 1 cDCs (cDC1s) and implicated in immune responses to viruses and cancer, recognises F-actin exposed on dead cell remnants and promotes cross-presentation of associated antigens. Here, we show that recruitment of phosphatase SHIP1, a process governed by a single amino acid residue adjacent to the signalling motif of the receptor, partly explains how DNGR-1 fails to trigger cDC1 activation in vitro. Substituting this residue converts DNGR-1 into an activating receptor but decreases induction of cross-presentation of dead cell-associated antigens. Introducing the reverse mutation into the related receptor Dectin-1 impairs its activation capacity while enhancing its ability to promote cross-presentation. These findings reveal a functional trade-off in receptor signalling and suggest that DNGR-1 has evolved to prioritise antigen cross-presentation over cellular activation, possibly to minimise inflammatory responses to dead cells.

2025-10-28 | GSE287030 | GEO

Targeting PAR2 reprograms myeloid cells to enhance antigen presentation and potentiate PD-1 checkpoint blockade therapy

Project description:Targeting PAR2 reprograms myeloid cells to enhance antigen presentation and potentiate PD-1 checkpoint blockade therapy

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Pharmacological Targeting of ALDH1a2 in Dendritic Cells Enhances Antigen Presentation, T Cell Activation and Anti-tumor immunity

Project description:Dendritic cell (DC) vaccines have been proposed as cancer immunotherapies due to their role as crucial antigen-presenting cells that regulate T cell functions. Despite considerable efforts to optimize ex vivo priming of DCs, DC vaccines have rarely been successful, suggesting the presence of unknown inhibitory factors. Here, we examined DC differentiation dynamics and discovered that ALDH1a2-produced retinoic acid (RA) acts as a bottleneck factor, initiating negative feedback to inhibit DC maturation. Removing this inhibition through either genetic knockout or pharmacological blockade using KyA33, an ALDH1a2 inhibitor we developed, significantly enhances DC maturation, phagocytosis, antigen presentation, and T cell activation, in part by downregulating glucose metabolism. KyA33 demonstrates favorable drug-like properties, including low toxicity, high membrane permeability, and low cell efflux rate. Its non-covalent binding to ALDH1A2 was also validated through X-ray crystallography. Importantly, application of KyA33 generates more robust DCs vaccines, promoting anti-tumor immunity through enhancing antigen-specific T cell responses. Our investigation highlights the intricate interplay between retinoid signaling, dendritic cell maturation, and immune metabolism, offering promising avenues for enhancing cancer immunotherapies.

2025-11-03 | MTBLS10389 | MetaboLights

Ferroptotic tumor cells revamp tumor-associated macrophage antigen presentation to unleash immune checkpoint blockade efficacy

Project description:Activation of antigen presentation has been shown to contribute to improved immunotherapy outcomes. Herein, we show that inducing tumor cell ferroptosis boosts anti-tumor immunity by potentiating major histocompatibility complex II (MHC-II)- dependent antigen presentation in tumor-infiltrating macrophages. Supporting our findings with multi-omics data, we reported that ferroptotic tumor-derived all-trans retinoic acid (ATRA) is a novel regulator of MHC-II in macrophages. ATRA directly targets CD38 through transcriptional factor RARα and activates master regulator TFEB to control MHC-II expression by inducing autophagy. Clinically, a ferroptosis signature is associated with better immunotherapy response. We also innovatively develop a drug-free nano-redox lever (DFNRL) to circumvent the non-specific limitations of conventional drugs, which specifically targets and disrupts glutathione metabolism in tumor cells by accepting electrons, thereby boosting ferroptosis-mediated immune stimulation. This synergizes with anti–PD-1 immunotherapy across preclinical models. Our study answers an unidentified role for ferroptosis in modulating anti-tumor immunity and provides a clinically translatable approach to enhance immunotherapy efficacy.

2026-03-15 | GSE318119 | GEO

Tumor-derived CDC37 inhibits antigen cross-presentation in dendritic cells and impairs anti-tumor immunity in breast cancer

Project description:Tumor mutational burden (TMB), usually representing high immunogenicity, could not always predict treatment response of immune checkpoint blockade (ICB). Here, we showed that defective antigen cross-presentation in type 1 conventional dendritic cells (cDC1) was responsible for lacking tumor-specific cytotoxic T lymphocytes (CTLs) in triple-negative breast cancer (TNBC) patients. Mechanistically, tumor cytosolic CDC37, shuttled via extracellular vesicles (EVs) into the endosomes of intratumor DCs, inhibited antigen cross-presentation by locking antigen binding to HSP90 and precluding their translocation from endosomes to cytoplasm. CDC37 knockdown in tumor cells or inhibiting CDC37/HSP90 interaction in DCs efficiently promoted antigen translocation and enhanced their cross-presentation, which improved ICB therapeutic responses. Clinically, high tumor CDC37 expression was associated with low infiltration of antigen-specific CTLs and poor ICB efficacy in TNBC patients. Therefore, tumor EV-shuttled CDC37 locks antigen/chaperone interaction and impairs antigen cross-presentation in DCs. Moreover, targeting CDC37 is promising to enhance anti-tumor immunity and reverse ICB resistance.

| PXD069576 |

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