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Targeting SNX9 rescues CD28-mediated T cell exhaustion for cancer immunotherapy

ABSTRACT: Targeting SNX9 rescues CD28-mediated T cell exhaustion for cancer immunotherapy

PROVIDER: PRJNA786531 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17139600.fastq.gz	Fastqsanger.gz
	SRR17139601.fastq.gz	Fastqsanger.gz
	SRR17139602.fastq.gz	Fastqsanger.gz
	SRR17139603.fastq.gz	Fastqsanger.gz
	SRR17139604.fastq.gz	Fastqsanger.gz

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Targeting SNX9 rescues CD28-mediated T cell exhaustion for cancer immunotherapy - Targeted Pooled CRISPR Screen for T cell Exhaustion

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Targeting SNX9 rescues CD28-mediated T cell exhaustion for cancer immunotherapy - Targeted Pooled CRISPR Screen for T cell Exhaustion

Project description:Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level. A pooled targeted CRISPR screen was performed on ex vivo exhausted T cells. The readout was elevated CD107a degranulation after repetitive stimulation (CD107a+ vs CD107- cells after 4h co-culture with peptide loaded tumor cells).

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Targeting SNX9 rescues CD28-mediated T cell exhaustion for cancer immunotherapy

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

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.

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