Dataset Information

Lymphodepleting chemotherapy potentiates neoantigen-directed T-cell therapy by enhancing antigen presentation

ABSTRACT: Adoptive cell therapy (ACT) targeting tumor-specific antigens holds promise for solid-tumors, but limited neoantigen presentation remains a key barrier to efficacy. Here, we identify and characterize a T-cell receptor (TCR), T104, for the KRAS.G12V mutation, a prevalent neoantigen in colorectal, lung, and pancreatic cancers. TCR-T104 selectively recognize and kill KRAS.G12V expressing tumor cells. Combining T-cell therapy with lymphodepleting chemotherapy significantly enhance tumor-cell killing, particularly by TCR-T-cells, tumor-infiltrating lymphocytes (TILs) and T-cell engager antibodies across multiple cancer types and target antigens. Mechanistically, chemotherapy upregulates immunoproteasome activity and HLA-I surface expression. HLA-Immunopeptidome analyses reveal that chemotherapy remodels the antigenic landscape across tumor cell-lines and In vivo models, increasing peptide abundance and hydrophobicity, while altering proteasomal cleavage preferences. These findings establish a synergistic role for chemotherapy in enhancing neoantigen presentation and T-cell-mediated tumor recognition and suggest that fine-tuning these regimens could improve ACT efficacy, particularly in tumors with low-abundance neoantigens. **Proteomics data have been deposited to the PRIDE (ProteomeXchange) repository under accession number PXD061178. This dataset expands on data previously deposited under accession PXD061178.Contains proteomic data of SW620 A03 as well HLA-1 Immunopeptidomic MIapaca2 cell line treated with Chemo and SW620 A03 tumors harvested from NSG mice treat with chemothetapy.**

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Cancer Cell Line, Colorectal Adenocarcinoma Cell Line, Miapaca-2 Cell, Sw-620 Cell, Permanent Cell Line Cell, Epithelial Cell

DISEASE(S): Colon Cancer,Pancreatic Cancer

SUBMITTER: Shira Sagie

LAB HEAD: Yardena Samuels

PROVIDER: PXD070607 | Pride | 2026-01-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	24105_DIANN_proteins.xlsx	Xlsx
	TTP_YS_24105_SW620_A0301-Chemo1_28052025_01-Jun-25_9334.d.zip	Other
	TTP_YS_24105_SW620_A0301-Chemo2_28052025_01-Jun-25_9333.d.zip	Other
	TTP_YS_24105_SW620_A0301-Chemo3_28052025_01-Jun-25_9337.d.zip	Other
	TTP_YS_24105_SW620_A0301-DMSO1_28052025_01-Jun-25_9336.d.zip	Other

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Publications

Lymphodepleting chemotherapy potentiates neoantigen-directed T cell therapy by enhancing antigen presentation.

Sagie Shira S Babu Tomer T Weller Chen C Tabachnik Claire C Livneh Ido I Quast Nele P NP Gumpert Nofar N Shomuradova Alina A Raybould Matthew I MI Levy Ronen R Malko Dmitry D Alfia Adi A Ben Lulu Talal T Alon Michal M Herrera Franco F Kutuzov Mikhail M Zerbib Mirie M Greenberg Polina P Wasserman-Bartov Talya T Benedek Gil G Levin Yishai Y Stossel Chani C Kamer Iris I Golan Talia T Oren Roni R Shmueli Merav M Bartok Osnat O Bar Jair J Cohen Jonathan J Dushek Omer O Deane Charlotte M CM Samuels Yardena Y

Cell reports. Medicine 20251201 12

Adoptive cell therapy (ACT) targeting tumor-specific antigens holds promise for solid tumors, but limited neoantigen presentation remains a key barrier to efficacy. Here, we identify and characterize a T cell receptor (TCR), T104, for the KRAS.G12V mutation, a prevalent neoantigen in colorectal, lung, and pancreatic cancers. TCR-T104 selectively recognizes and kills KRAS.G12V-expressing tumor cells. Combining T cell therapy with lymphodepleting chemotherapy significantly enhances tumor cell kill ...[more]

PMID: 41406943

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.