Zhang and Fritsche et al. created an RNA A→I editome peptide database, and combined LC-MS with RNAseq to demonstrate that RNA editing via ADAR1 creates immunogenic peptides in multiple melanoma tumors. The edited peptides induced an HLA-restricted and antigen-specific T cell response, which led to target cell killing in vitro. For the edited peptides, mRNA levels corresponded with peptide levels and could be used as a surrogate for RNA editing. RNAseq showed that edited peptides were present in healthy tissues, but were overexpressed in tumors, particularly in ovarian cancer, breast cancer, kidney cancer, and melanoma.
In addition to genomic mutations, RNA editing is another major mechanism creating sequence variations in proteins by introducing nucleotide changes in mRNA sequences. Deregulated RNA editing contributes to different types of human diseases, including cancers. Here we report that peptides generated as a consequence of RNA editing are indeed naturally presented by human leukocyte antigen (HLA) molecules. We provide evidence that effector CD8(+) T cells specific for edited peptides derived from cyclin I are present in human tumours and attack tumour cells that are presenting these epitopes. We show that subpopulations of cancer patients have increased peptide levels and that levels of edited RNA correlate with peptide copy numbers. These findings demonstrate that RNA editing extends the classes of HLA presented self-antigens and that these antigens can be recognised by the immune system.
Author Info: (1) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (2) Immatics Biotechnologies,
Author Info: (1) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (2) Immatics Biotechnologies, Paul-Ehrlich-Str 15, 72076, Tubingen, Germany. (3) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (4) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (5) Department of Bioinformatics and Computation Biology, The University of Texas MD Anderson Cancer Center, P. O. Box 301402, Houston, TX, 77230, USA. (6) Department of Bioinformatics and Computation Biology, The University of Texas MD Anderson Cancer Center, P. O. Box 301402, Houston, TX, 77230, USA. (7) Immatics US, 2130W Holcombe Blvd, Houston, TX, 77030, USA. (8) Immatics Biotechnologies, Paul-Ehrlich-Str 15, 72076, Tubingen, Germany. (9) Immatics Biotechnologies, Paul-Ehrlich-Str 15, 72076, Tubingen, Germany. (10) Immatics Biotechnologies, Paul-Ehrlich-Str 15, 72076, Tubingen, Germany. (11) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (12) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (13) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (14) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (15) Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, 6431 Fannin Street MSB 6.200, Houston, TX, 77030, USA. (16) Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, BCM225, Houston, TX, 77030, USA. (17) Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, BCM225, Houston, TX, 77030, USA. (18) Department of Bioinformatics and Computation Biology, The University of Texas MD Anderson Cancer Center, P. O. Box 301402, Houston, TX, 77230, USA. Department of Pathophysiology, College of Basic Medicine, China Medical University, Shenyang, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122, China. (19) Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, BCM225, Houston, TX, 77030, USA. (20) Immatics Biotechnologies, Paul-Ehrlich-Str 15, 72076, Tubingen, Germany. Immatics US, 2130W Holcombe Blvd, Houston, TX, 77030, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. (22) Department of Bioinformatics and Computation Biology, The University of Texas MD Anderson Cancer Center, P. O. Box 301402, Houston, TX, 77230, USA. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77230, USA. (23) Immatics Biotechnologies, Paul-Ehrlich-Str 15, 72076, Tubingen, Germany. weinschenk@immatics.com. Immatics US, 2130W Holcombe Blvd, Houston, TX, 77030, USA. weinschenk@immatics.com. (24) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77230, USA. gmills@mdanderson.org. (25) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Unit 904, Houston, TX, 77054, USA. phwu@mdanderson.org.
