CD4 <sup>+</sup> T cells with convergent TCR recombination reprogram stroma and halt tumor progression in adoptive therapy
Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4<sup>+</sup> T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II-negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4<sup>+</sup> T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.
Authors
- Hans Schreiber (ORCID: https://orcid.org/0000-0002-1908-6233)
- Karin Schreiber (ORCID: https://orcid.org/0009-0000-1414-9365)
- Madeline Steiner (ORCID: https://orcid.org/0000-0002-6201-4390)
- Kazuma Kiyotani (ORCID: https://orcid.org/0000-0002-9236-9061)
- Matthias Leisegang (ORCID: https://orcid.org/0000-0003-3692-7142)
- Steven P. Wolf (ORCID: https://orcid.org/0009-0008-2723-695X)
- Leonie Rosenberger
- Andrea Schietinger (ORCID: https://orcid.org/0000-0003-3644-1687)
- Yifei Hu (ORCID: https://orcid.org/0000-0003-2870-7772)
- Jun Huang (ORCID: https://orcid.org/0000-0003-0271-4384)
- V.C.J. Wallace (ORCID: https://orcid.org/0009-0005-9716-7943)
- Yusuke Nakamura (ORCID: https://orcid.org/0000-0003-2956-382X)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Chicago (US)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Japanese Foundation For Cancer Research (JP)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1126/sciimmunol.adp6529
- Citations
- 7
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.98
Funders
- National Institutes of Health