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Proteostatic Stress Response Drives T Cell Exhaustion and Immune Evasion

ABSTRACT: Proteostatic Stress Response Drives T Cell Exhaustion and Immune Evasion

PROVIDER: PRJNA1295348 | ENA |

REPOSITORIES: ENA

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Proteostatic Stress Response Drives T Cell Exhaustion and Immune Evasion

Project description:Chronic infections and cancer cause T cell dysfunction known as exhaustion due to persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors, which dampens protective immunity and limits the efficacy of immunotherapies1-4. The mechanisms behind T cell exhaustion remain poorly understood. Herein, we dissected the proteome of CD8+ exhausted T cells (Tex) across multiple states of exhaustion in the context of both chronic viral infections and cancer. We found that there was a non-stochastic pathway-specific discordance between mRNA and protein dynamics in T effector (Teff) versus Tex cells. We identified a unique proteostatic stress response (PSR) in Tex cells which we termed TexPSR. Contrary to canonical stress responses with reduced protein synthesis5,6, the TexPSR involves increased global translation activity and an upregulation of specialized chaperones, characterized further by the accumulation of protein aggregates, stress granules and autophagy-dominant protein catabolism. We established that disruption of proteostasis alone can convert Teff to Tex cells, and linked TexPSR mechanistically to persistent Akt signaling. Finally, we found that disruption of TexPSR-associated chaperones in CD8+ T cells improved cancer immunotherapy preclinically and demonstrated that high TexPSR feature in T cells in cancer patients confers poor response to immunotherapy clinically. Our findings collectively highlight TexPSR as a hallmark and a mechanistic driver of T cell exhaustion, raising the possibility of targeting proteostasis as a potential novel approach for cancer immunotherapy.

2025-07-23 | GSE303401 | GEO

Lactate sensing drives fungal immune evasion

Project description:Lactate sensing drives fungal immune evasion

| PRJEB13396 | ENA

Proteostatic Stress Response is a Mechanistic Driver of T Cell Exhaustion and a New Therapeutic Opportunity for Cancer Immunotherapy

2025-07-22 | MSV000098609 | MassIVE

A tumor specific super-enhancer drives immune evasion by guiding synchronous expression of PD-L1 and PD-L2

Project description:A tumor specific super-enhancer drives immune evasion by guiding synchronous expression of PD-L1 and PD-L2

2019-07-30 | GSE135016 | GEO

Tumor-intrinsic ETV5 Expression Promotes MDSCs-mediated Immune Evasion and Immune Checkpoint Inhibitor Resistance

Project description:Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Patients with tumors expressing high levels of ETV5 respond poorly to immunotherapy, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of MDSCs. Knockdown of ETV5 in tumor cells reduces the generation of MDSCs from myeloid progenitors and their accumulation in the tumor microenvironment, leading to enhanced anti-tumor response presented by increased T cell infiltration, proliferation and reduced exhaustion. Mechanistically, ETV5 binds to JAK2 protein, facilitates its dimerization and elevates its phosphorylation status. Consequently, this promotes the phosphorylation of STAT3, which activates the transcription of CCL2, augmenting the recruitment of MDSCs. Finally, ETV5 deficiency reduces MDSCs and enriches anticancer T lymphocytes, thereby improving ICI efficacy in mice. Our findings shed light on the crucial role of tumor-intrinsic ETV5 in facilitating immune evasion and its fundamental mechanism. Furthermore, they offer a novel immunotherapy strategy targeting ETV5 for the treatment of solid tumors.

2026-02-03 | GSE286508 | GEO

Neurons shift translational control to secure proteostatic resilience during ER stress

Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.

2022-06-13 | GSE200742 | GEO

ZNF296 drives immune evasion in epithelial cancer cells [RNA-seq]

Project description:ZNF296 drives immune evasion in epithelial cancer cells [RNA-seq]

| PRJNA1191517 | ENA

ZNF296 drives immune evasion in epithelial cancer cells [ChIP-seq]

Project description:ZNF296 drives immune evasion in epithelial cancer cells [ChIP-seq]

| PRJNA1191519 | ENA

ZNF296 drives immune evasion in epithelial cancer cells [ATAC-seq]

Project description:ZNF296 drives immune evasion in epithelial cancer cells [ATAC-seq]

| PRJNA1191518 | ENA

Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

Project description:Reversible mitochondrial dysfunction drives terminal T-cell exhaustion