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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

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

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

Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

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

| PRJNA575910 | ENA

Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas

Project description:Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas

| PRJNA773062 | ENA

KRAS drives immune evasion in a genetic model of pancreatic cancer

Project description:KRAS drives immune evasion in a genetic model of pancreatic cancer

| PRJNA548394 | ENA

Mal2 drives immune evasion by reducing antigen presentation on tumor cells

Project description:Mal2 drives immune evasion by reducing antigen presentation on tumor cells

| PRJNA602751 | ENA

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

Project description:Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

| PRJNA1077265 | ENA

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

Project description:MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

2024-04-15 | GSE255930 | GEO

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