In a meta-cohort (n=117) of matched hepatocellular carcinoma (HCC) and healthy tissue RNAseq datasets, Camarena et al. quantified gene expression, reconstructed non-annotated transcripts, and determined the tumor-specific transcriptome in each patient. Utilizing HCC RiboSeq data predicted the translation rate of long non-coding RNAs and novel transcripts. The ratio between tumor- and normal-specific transcripts was significantly higher in non-coding than coding transcripts, and ~40% of the tumor-specific antigens in HCC were derived from noncanonical (nc) ORFs. Some ncORFs were shared by more than 10% of the patients, and predicted peptides bound to HLA in vitro and demonstrated immunogenicity in HDD-DR1 mice.
Contributed by Ute Burkhardt
ABSTRACT: The expression of tumor-specific antigens during cancer progression can trigger an immune response against the tumor. Here, we investigate if microproteins encoded by noncanonical open reading frames (ncORFs) are a relevant source of tumor-specific antigens. We analyze RNA sequencing data from 117 hepatocellular carcinoma (HCC) tumors and matched healthy tissue together with ribosome profiling and immunopeptidomics data. Combining human leukocyte antigen-epitope binding predictions and experimental validation experiments, we conclude that around 40% of the tumor-specific antigens in HCC are likely to be derived from ncORFs, including two peptides that can trigger an immune response in humanized mice. We identify a subset of 33 tumor-specific long noncoding RNAs expressing novel cancer antigens shared by more than 10% of the HCC samples analyzed, which, when combined, cover a large proportion of the patients. The results of the study open avenues for extending the range of anticancer vaccines.
Author Info: (1) Hospital del Mar Research Institute, Barcelona, Spain. (2) Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. (3) Center for Applied Med
Author Info: (1) Hospital del Mar Research Institute, Barcelona, Spain. (2) Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. (3) Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. (4) Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany. (5) Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain. (6) Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain. (7) Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. (8) Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. Centro de Investigacin Biomdica en Red de Enfermedades Hepticas y Digestivas (CIBEREHD), Pamplona, Spain. Instituto de Investigacin Sanitaria de Navarra (IdiSNA), Pamplona, Spain. Cancer Clinic University of Navarra (CCUN), Pamplona, Spain. (9) Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. Centro de Investigacin Biomdica en Red de Enfermedades Hepticas y Digestivas (CIBEREHD), Pamplona, Spain. Instituto de Investigacin Sanitaria de Navarra (IdiSNA), Pamplona, Spain. Cancer Clinic University of Navarra (CCUN), Pamplona, Spain. Spanish Network for Advanced Therapies (TERAV ISCIII), Madrid, Spain. (10) Hospital del Mar Research Institute, Barcelona, Spain. (11) Hospital del Mar Research Institute, Barcelona, Spain. Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain.
