To better characterize tumor antigens in cancer and metastases, Kalaora et al. used a combination of whole exome sequencing, neoantigen prediction, HLA-I and -II peptidome analysis, TIL functional analysis, and TCR sequencing. Analyzing 15 tumors from 7 melanoma patients and one melanoma cell line, the researchers identified similarities in tumor-associated antigen (TAA), neoantigen, and TIL TCR profiles between metastases within the same patient. TILs were reactive to a small set of neoantigens and to multiple TAAs. Neoantigen-specific TILs induced killing of up to 90% of matched melanoma cells in vitro and in vivo.
The quest for tumor-associated-antigens (TAAs) and neo-antigens is a major focus of cancer immunotherapy. Here we combine a neo-antigen prediction-pipeline and human-leukocyte-antigen (HLA)-peptidomics to identify TAAs and neo-antigens in 16 tumors derived from seven melanoma patients, and characterize their interactions with their TILs. Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neo-antigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell co-signatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neo-antigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neo-antigen-specific T-cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA-peptidomics with neo-antigen predictions allows robust identification of targetable neo-antigens, which could successfully guide personalized cancer-immunotherapies.
Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science Yardena.Samuels@weizmann.ac.il. (2) Department of Molecular Cell Biology, Weizmann Institute of Science. (3)
Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science Yardena.Samuels@weizmann.ac.il. (2) Department of Molecular Cell Biology, Weizmann Institute of Science. (3) Department of Molecular Cell Biology, Weizmann Institute of Science. (4) Department of Immunology, Weizmann Institute of Science. (5) Biology, Technion - Israel Intitute of Technology. (6) Department of Immunology, Weizmann Institute of Science. (7) Department of Immunology, Weizmann Institute of Science. (8) Department of Molecular Cell Biology, Weizmann Institute of Science. (9) Surgical Oncology and Genomic Medicine, University of Texas MD Anderson Cancer Center. (10) Center for Bioinformatics and Computational Biology, University of Maryland, College Park. (11) Department of Molecular Cell Biology, Weizmann Institute of Science. (12) TCR Discovery, BioNTech Cell & Gene Therapies GmbH. (13) TCR Discovery, BioNTech Cell & Gene Therapies GmbH. (14) Molecular Cell Biology, The Weizmann Institute of Science. (15) Department of Life Sciences Core Facilities, Weizmann Institute of Science. (16) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center. (17) Genomic Medicine, University of Texas MD Anderson Cancer Center. (18) Genomic Medicine, University of Texas MD Anderson Cancer Center. (19) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (20) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (21) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (22) Department of Systems Biology, University of Texas MD Anderson Cancer Center. (23) Department of Molecular Cell Biology, Weizmann Institute of Science. (24) Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center. (25) Translational Medicine, MedImmune. (26) Surgery Branch, National Cancer Institute. (27) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (28) Immunotherapy, TRON gGmbH. (29) Department of Immunology, weizmann INstitute. (30) CCR, NCI, NIH. (31) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. (32) Department of Immunology, Weizmann Institute of Science. (33) Biology, Technion - Israel Intitute of Technology.
