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

Sci Transl Med. 2022 Aug 31;14(660):eabo6135. doi: 10.1126/scitranslmed.abo6135. Epub 2022 Aug 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm
  • Cell Line, Tumor
  • Cell- and Tissue-Based Therapy
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Proteomics
  • Receptors, Antigen, T-Cell* / metabolism
  • Receptors, Antigen, T-Cell* / therapeutic use
  • T-Lymphocytes*


  • Antigens, Neoplasm
  • Receptors, Antigen, T-Cell