Over a decade ago, autologous TIL therapy led to a complete, ongoing response in a patient with stage IV melanoma. These TILs included MEL8, a dominant Melan A-reactive T cell clonotype that cross-reacted with other HLA-matched tumor types, including types not expressing Melan A. A novel proteome database predicted MEL8 TCR targets, with three of the top four (Melan A, BST2, and IMP2) confirmed functionally. These peptides shared similar core sequences and HLA–TCR conformations, and increased MEL8 T cell activation when combined in target cells versus one alone. PBMCs primed with any peptide were cross-reactive to all three. Such “multi-pronged” T cells were found in diverse cancer types.
Contributed by Alex Najibi
ABSTRACT: The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A(_)02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.
Author Info: (1) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (2) Division of Infection and Immunity, Cardiff University School of Med
Author Info: (1) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (2) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (3) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (4) Systems Immunology Research Institute, Cardiff, Wales CF14 4XN, UK. (5) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (6) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (7) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (8) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (9) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (10) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (11) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (12) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (13) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (14) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (15) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (16) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (17) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (18) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (19) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (20) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (21) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (22) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (23) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (24) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (25) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (26) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (27) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK; National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (28) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (29) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (30) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (31) The Zeeman Institute, University of Warwick, Coventry CV4 7AL, UK. (32) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK. (33) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK; Systems Immunology Research Institute, Cardiff, Wales CF14 4XN, UK. Electronic address: sewellak@cardiff.ac.uk.
