PXD061178

PXD061178 is an original dataset announced via ProteomeXchange.

Title	TCR targeting of KRAS G12V/C neoantigens is enhanced by lymphodepleting chemotherapy
Description	Lung cancer remains the leading cause of cancer-related deaths worldwide. Immunotherapy agents have doubled treatment response rates in non-small cell lung cancer (NSCLC). However, these responses are neither universal nor consistently durable, underscoring the need for innovative therapeutic strategies. Using a data-driven approach, we identified and characterized an immunogenic neopeptide derived from the KRAS.G12V mutation, prevalent in lung, colon, and pancreatic cancers. We isolated a cognate TCR, T104, which targets and kills cancer cells expressing KRAS G12V. Moreover, TCR-T104 proved to cross-react with the KRAS.G12C neoantigen via a hydrophobic pocket and kill cancer cells expressing this prevalent KRAS mutant. Combining TCR therapy with lymphodepleting chemotherapy using fludarabine and cyclophosphamide resulted in synergistic antitumor effects against multiple neoantigens. HLA-immunopeptidomics revealed that chemotherapy modulates the cell immunopeptidome and enhances target peptide presentation, likely through immunoproteasome activation and HLA-I elevation. These findings suggest a new mechanism explaining the combined efficacy of chemotherapy and immunotherapy.
HostingRepository	PRIDE
AnnounceDate	2025-10-03
AnnouncementXML	Submission_2025-10-03_04:34:39.161.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shira Sagie
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF; timsTOF

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-25 07:24:56	ID requested
⏵ 1	2025-10-03 04:34:39	announced

Dataset with its publication pending

ProteomeXchange project tag: Cancer (B/D-HPP), Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

submitter keyword: lymphodepleting chemotherapy, Lung cancer, KRAS G12V, KRAS G12C, TCR therapy, neoantigens, colon cancer.,Adoptive cell therapy, pancreatic cancer

Yardena Samuels
contact affiliation	Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
contact email	yardena.samuels@weizmann.ac.il
lab head
Shira Sagie
contact affiliation	The Weizmann Institute of Science
contact email	shira.sagie-groher@weizmann.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061178
     1. Label: PRIDE project
     2. Name: TCR targeting of KRAS G12V/C neoantigens is enhanced by lymphodepleting chemotherapy