PMID- 16247014 OWN - NLM STAT- MEDLINE DCOM- 20051221 LR - 20220331 IS - 0027-8424 (Print) IS - 1091-6490 (Electronic) IS - 0027-8424 (Linking) VI - 102 IP - 44 DP - 2005 Nov 1 TI - The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. PG - 16013-8 AB - Our understanding of pathways leading to antitumor immunity may depend on an undistorted knowledge of the primary antigenic targets of patients' autologous T cell responses. In the melanoma model derived from patient DT, we applied cryopreserved short-term autologous mixed lymphocyte-tumor cell cultures (MLTCs) in combination with an IFN-gamma enzyme-linked immunospot (ELISPOT) assay to cDNA expression screening. We identified three previously unknown peptides processed from melanosomal proteins tyrosinase (presented by HLA-A(*)2601 and -B(*)3801) and gp100 (presented by HLA-B(*)07021) and five neoantigens generated by somatic point mutations in the patient's melanoma. The mutations were found in the genes SIRT2, GPNMB, SNRP116, SNRPD1, and RBAF600. Peptides containing the mutated residues were presented by HLA-A(*)03011, -B(*)07021, and -B(*)3801. Mutation-induced functional impairment was so far demonstrated for SIRT2. Within MLTC responder populations that were independently expanded from the patient's peripheral blood lymphocytes of different years, T cells against mutated epitopes clearly predominated. These results document a high degree of individuality for the cellular antitumor response and support the need for individualizing the monitoring and therapeutic approaches to the primary targets of the autologous T cell response, which may finally lead to a more effective cancer immunotherapy. FAU - Lennerz, Volker AU - Lennerz V AD - Department of Medicine, Hematology/Oncology, Johannes Gutenberg University, Langenbeckstrasse 1, D-55101 Mainz, Germany. FAU - Fatho, Martina AU - Fatho M FAU - Gentilini, Chiara AU - Gentilini C FAU - Frye, Roy A AU - Frye RA FAU - Lifke, Alexander AU - Lifke A FAU - Ferel, Dorothea AU - Ferel D FAU - Wolfel, Catherine AU - Wolfel C FAU - Huber, Christoph AU - Huber C FAU - Wolfel, Thomas AU - Wolfel T LA - eng SI - GENBANK/AJ505014 SI - GENBANK/AJ505015 SI - GENBANK/AJ505016 SI - GENBANK/AJ505017 SI - GENBANK/AJ577268 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20051024 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antigens, Neoplasm) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA Antigens) RN - 82115-62-6 (Interferon-gamma) SB - IM MH - Adult MH - Antigen Presentation MH - Antigens, Neoplasm/*genetics/immunology MH - Base Sequence MH - Coculture Techniques MH - Epitopes, T-Lymphocyte MH - Female MH - HLA Antigens/immunology MH - Humans MH - Interferon-gamma/analysis MH - Melanoma/*immunology/pathology MH - Molecular Sequence Data MH - *Point Mutation MH - T-Lymphocytes/cytology/*immunology MH - Tumor Cells, Cultured PMC - PMC1266037 EDAT- 2005/10/26 09:00 MHDA- 2005/12/22 09:00 PMCR- 2005/11/01 CRDT- 2005/10/26 09:00 PHST- 2005/10/26 09:00 [pubmed] PHST- 2005/12/22 09:00 [medline] PHST- 2005/10/26 09:00 [entrez] PHST- 2005/11/01 00:00 [pmc-release] AID - 0500090102 [pii] AID - 010216013 [pii] AID - 10.1073/pnas.0500090102 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16013-8. doi: 10.1073/pnas.0500090102. Epub 2005 Oct 24.