Dataset Information

VESTIGIAL-LIKE 1 IS A SHARED TARGETABLE CANCER-PLACENTA ANTIGEN EXPRESSED BY PANCREATIC AND BASAL-LIKE BREAST CANCERS

ABSTRACT: Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regression by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from tumor specimens of 35 PDAC patients. This led to the identification of a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1), a novel putative TAA demonstrating overexpression in multiple tumor types and low or absent transcript expression in essential normal tissues. VGLL1-specific CTLs isolated and expanded from the blood of a male PDAC patient showed the capacity to recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung and basal-like breast cancers. Gene expression profiling revealed that VGLL1 is a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic TAA targets for patients with multiple different cancer types.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Gregory Lizee

LAB HEAD: Greg Lizee

PROVIDER: PXD018302 | Pride | 2020-10-19

REPOSITORIES: Pride

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Publications

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.

Bradley Sherille D SD Talukder Amjad H AH Lai Ivy I Davis Rebecca R Alvarez Hector H Tiriac Herve H Zhang Minying M Chiu Yulun Y Melendez Brenda B Jackson Kyle R KR Katailiha Arjun A Sonnemann Heather M HM Li Fenge F Kang Yaan Y Qiao Na N Pan Bih-Fang BF Lorenzi Philip L PL Hurd Mark M Mittendorf Elizabeth A EA Peterson Christine B CB Javle Milind M Bristow Christopher C Kim Michael M Tuveson David A DA Hawke David D Kopetz Scott S Wolff Robert A RA Hwu Patrick P Maitra Anirban A Roszik Jason J Yee Cassian C Lizée Gregory G

Nature communications 20201021 1

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overe ...[more]

PMID: 33087697

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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.

Dataset Information

VESTIGIAL-LIKE 1 IS A SHARED TARGETABLE CANCER-PLACENTA ANTIGEN EXPRESSED BY PANCREATIC AND BASAL-LIKE BREAST CANCERS

Publications

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.

Similar Datasets

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