Wolf et al. characterized mL9-I-Ek-tetramer+ CD4+ TCRs in mice inoculated with MHC II-negative 6132A cancer cells expressing the mutated ribosomal protein L9 (mL9). Several different TCR clonotypes found in at least 3 to 4 of 6 different mice encoded identical TCRs (convergent recombination). These preferentially selected TCRs and TCRs derived from single T cell clonotypes that shared CDR elements in both α- and β-chains with preferentially selected TCRs were able to cause tumor destruction and growth arrest upon transduction into CD4+ T cells (CD4TCR). Adoptively transferred CD4TCRs targeted the tumor stroma and reprogrammed TAMs.
Contributed by Ute Burkhardt
ABSTRACT: Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4+ 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+ 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.
Author Info: (1) David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA. Department of Pathology, University of Chicago, Chicago, IL, USA. (2) David and Etta
Author Info: (1) David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA. Department of Pathology, University of Chicago, Chicago, IL, USA. (2) David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA. Institute of Immunology, Charit-Universittsmedizin Berlin, Campus Berlin Buch, Berlin, Germany. German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany. (3) Department of Pathology, University of Chicago, Chicago, IL, USA. (4) Department of Pathology, University of Chicago, Chicago, IL, USA. (5) Project for Immunogenomics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Laboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics (CiDIG), National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-shi, Osaka, Japan. (6) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Pritzker School of Medicine, University of Chicago, Chicago, IL, USA. (7) Institute of Immunology, Charit-Universittsmedizin Berlin, Campus Berlin Buch, Berlin, Germany. (8) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Committees on Cancer Biology and Immunology and Cancer Center, University of Chicago, Chicago, IL, USA. (9) David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA. Department of Pathology, University of Chicago, Chicago, IL, USA. (10) Project for Immunogenomics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Laboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics (CiDIG), National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-shi, Osaka, Japan. (11) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA. Department of Pathology, University of Chicago, Chicago, IL, USA. Committees on Cancer Biology and Immunology and Cancer Center, University of Chicago, Chicago, IL, USA.
