PXD066433
PXD066433 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Proteostatic Stress Response is a Mechanistic Driver of T Cell Exhaustion and a New Therapeutic Opportunity for Cancer Immunotherapy |
| 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. |
| HostingRepository | MassIVE |
| AnnounceDate | 2025-10-01 |
| AnnouncementXML | Submission_2025-10-01_09:20:33.156.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Brian Searle |
| SpeciesList | scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090; scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Carbamidomethyl |
| Instrument | Orbitrap Exploris 480; Orbitrap Fusion |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2025-07-22 19:06:36 | ID requested | |
| ⏵ 1 | 2025-10-01 09:20:33 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: data independent acquisition, T Cell Exhaustion, cancer, proteostasis, DatasetType:Proteomics |
Contact List
| Zihai Li | |
|---|---|
| contact affiliation | The Ohio State University |
| contact email | Zihai.Li@osumc.edu |
| lab head | |
| Brian C Searle | |
| contact affiliation | Mayo Clinic |
| contact email | searle.brian@mayo.edu |
| lab head | |
| Brian Searle | |
| contact affiliation | Mayo Clinic |
| contact email | searleb@gmail.com |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive-ftp.ucsd.edu/v10/MSV000098609/ |
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