Quantitative immunopeptidomics reveals a tumor stroma-specific target for T cell therapy

Gloria B. Kim, Jens Fritsche, Sebastian Bunk, Andrea Mahr, Felix Unverdorben, Kevin Tosh, Hong Kong, Colby R. Maldini, Chui Lau, Sriram Srivatsa, Shuguang Jiang, Joshua Glover, Derek Dopkin, Carolyn X. Zhang, Heiko Schuster, Daniel J. Kowalewski, Valentina Goldfinger, Martina Ott, David Fuhrmann, Maike BauesHans Boesmueller, Christoph Schraeder, Gisela Schimmack, Colette Song, Franziska Hoffgaard, Michael Roemer, Chih Chiang Tsou, Martin Hofmann, Thomas Treiber, Meike Hutt, Leonie Alten, Maike Jaworski, Amir Alpert, Sarah Missel, Carsten Reinhardt, Harpreet Singh, Oliver Schoor, Steffen Walter, Claudia Wagner, Dominik Maurer, Toni Weinschenk, James L. Riley

Research output: Contribution to journalArticlepeer-review


T cell receptor (TCR)-based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide-human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ∼1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI α-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.

Original languageEnglish (US)
Article numberabo6135
JournalScience translational medicine
Issue number660
StatePublished - Aug 31 2022

ASJC Scopus subject areas

  • Medicine(all)


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