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A post-transcriptional regulatory checkpoint restrains acquisition of cytotoxic activity in tumor-infiltrating CD4+ T cells

ABSTRACT: A post-transcriptional regulatory checkpoint restrains acquisition of cytotoxic activity in tumor-infiltrating CD4+ T cells

PROVIDER: PRJNA958099 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24236245.fastq.gz	Fastqsanger.gz
	SRR24236246.fastq.gz	Fastqsanger.gz
	SRR24236247.fastq.gz	Fastqsanger.gz
	SRR24236248.fastq.gz	Fastqsanger.gz
	SRR24236249.fastq.gz	Fastqsanger.gz

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A post-transcriptional regulatory checkpoint restrains acquisition of cytotoxic activity in tumor-infiltrating CD4+ T cells

Project description:Tumor-infiltrating cytotoxic CD4+ T cells (TCTX) are a promising therapeutic target, but how their activity is regulated is poorly understood. Here, we show that a post-transcriptional checkpoint restrains TCTX activity in suppressive tumor microenvironments. In untreated tumors, poised TCTX express high levels of Gzmb mRNA but produce little Granzyme B (GzmB) protein. Differentiation into poised TCTX is regulated by the Blimp-1-Bcl6 axis and requires type I interferon signaling. GzmB protein is produced by tumor-infiltrating TCTX upon treatment with TREG-depleting aCTLA-4 antibodies and following blockade of LAG-3 and PD-1. These treatments downregulate Zfp36l1, encoding an RNA binding protein. Deletion of Zfp36l1 and its paralog Zfp36 increases GzmB protein in CD4+ T cells in untreated tumors and reduces tumor mass. These results demonstrate that TCTX activity is restrained in tumors through LAG-3 and PD-1 and the ZFP36 family of RNA binding proteins. We propose that these pathways represent targets for therapeutic intervention.

2024-12-19 | GSE230230 | GEO

Interleukin-27 signaling serves as an immunological checkpoint for innate cytotoxic cells to promote hepatocellular carcinoma

Project description:While some of the inflammatory mechanisms driving hepatocellular carcinoma (HCC) had been proposed, the regulators of anti-cancer immunity in HCC remain poorly understood. We found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. High IL-27EBI3 or IL-27RA expression correlated with poor prognosis for patients with HCC. Loss of IL-27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL-27R signaling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL-27R ablation enhanced the accumulation and activation, while depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL-27R disruption. Pharmacological neutralization of IL-27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL-27R signaling as an immunological checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL-27 pathway blockade in HCC

2022-05-27 | GSE200040 | GEO

Tissue-infiltrating cytotoxic T cells and endothelial cell apoptosis in systemic sclerosis

Project description:Tissue-infiltrating cytotoxic T cells and endothelial cell apoptosis in systemic sclerosis

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Regulatory T cells restrain IL-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cells

Project description:In addition to helper and regulatory potential, CD4+T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+T cells following immunotherapy. CD4 transfer into lymphodepleted animals or regulatory T cell (Treg)depletion promoted GzmB expression by tumor-infiltrating CD4+which was prevented by IL-2 neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized bythe expression of the transcription factors T-bet and Blimp-1. Whilst T-bet ablation restrictedIFN-gproduction, lossof Blimp-1preventedGzmB expressionin response to IL-2, suggesting these are two independent programs required forpolyfunctionality of tumor-reactive CD4+T cells. The data underscores the role of Treg, IL-2 and Blimp-1 controlling the differentiation of cytotoxic T cells and offers a pathway to enhancement of anti-tumor activity through their manipulation.

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Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ tumor-infiltrating T cells

Project description:An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.

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Targeting ERAP enhances anti-tumor immunity by disrupting the NKG2A/HLA-E inhibitory checkpoint

Project description:New targets that enhance anti-tumor immunity must be identified to improve the efficacy of cancer immunotherapy. Here we show that loss of endoplasmic reticulum aminopeptidase (ERAP) family proteins improves anti-tumor immunity and synergizes with immune checkpoint blockade. Mechanistically, we show that loss of ERAP inactivates the HLA-E/NKG2A checkpoint, which normally restrains tumor killing by both CD8+ T cells and NK cells. The inhibitory activity of HLA-E is dependent on its presentation of a restricted set of invariant epitopes which form the binding surface for the NKG2A/CD94 receptor complex. Using genetic screening, in vivo models, cell-based assays, and immunopeptidomics, we show that loss of ERAP activity prevents the processing of these invariant peptides and alters the presented peptidome of both HLA-E and classical MHC-I. HLA-E neo-peptides presented after ERAP deletion are unable to bind the NKG2A/CD94 receptor, rendering tumor cells highly susceptible to killing by NKG2A+ cytotoxic T and NK cells. Thus, loss of ERAP phenocopies the loss or inhibition of the HLA-E/NKG2A pathway and represents an attractive therapeutic approach to inhibit this critical checkpoint. More broadly, this work identifies ERAP1/2 as druggable intracellular enzymes that could be targeted using small molecules to inactivate a cell-surface inhibitory pathway and represents a novel approach to therapeutic modulation of immune responses.

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