Chimeric RNAs reveal putative neoantigen peptides for developing tumor vaccines for breast cancer.

Autor:	Mistretta B; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States., Rankothgedera S; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States., Castillo M; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States., Rao M; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States., Holloway K; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States., Bhardwaj A; Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, United States., El Noafal M; Department of Medicine, Houston Methodist Research Institute, Houston, TX, United States., Albarracin C; Department of Pathology, The UT MD Anderson Cancer Center, Houston, TX, United States., El-Zein R; Department of Medicine, Houston Methodist Research Institute, Houston, TX, United States., Rezaei H; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States., Su X; Department of Bioinformatics & Computational Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, United States., Akbani R; Department of Bioinformatics & Computational Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, United States., Shao XM; Biomedical Engineering Department, Institute for Computational Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States., Czerniecki BJ; Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, United States., Karchin R; Biomedical Engineering Department, Institute for Computational Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States., Bedrosian I; Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, United States., Gunaratne PH; Department of Biology & Biochemistry, University of Houston, Houston, TX, United States.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States.; Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Sep 06; Vol. 14, pp. 1188831. Date of Electronic Publication: 2023 Sep 06 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1188831
Abstrakt:	Introduction: We present here a strategy to identify immunogenic neoantigen candidates from unique amino acid sequences at the junctions of fusion proteins which can serve as targets in the development of tumor vaccines for the treatment of breastcancer. Method: We mined the sequence reads of breast tumor tissue that are usually discarded as discordant paired-end reads and discovered cancer specific fusion transcripts using tissue from cancer free controls as reference. Binding affinity predictions of novel peptide sequences crossing the fusion junction were analyzed by the MHC Class I binding predictor, MHCnuggets. CD8+ T cell responses against the 15 peptides were assessed through in vitro Enzyme Linked Immunospot (ELISpot). Results: We uncovered 20 novel fusion transcripts from 75 breast tumors of 3 subtypes: TNBC, HER2+, and HR+. Of these, the NSFP1-LRRC37A2 fusion transcript was selected for further study. The 3833 bp chimeric RNA predicted by the consensus fusion junction sequence is consistent with a read-through transcription of the 5'-gene NSFP1-Pseudo gene NSFP1 (NSFtruncation at exon 12/13) followed by trans-splicing to connect withLRRC37A2 located immediately 3' through exon 1/2. A total of 15 different 8-mer neoantigen peptides discovered from the NSFP1 and LRRC37A2 truncations were predicted to bind to a total of 35 unique MHC class I alleles with a binding affinity of IC50<500nM.); 1 of which elicited a robust immune response. Conclusion: Our data provides a framework to identify immunogenic neoantigen candidates from fusion transcripts and suggests a potential vaccine strategy to target the immunogenic neopeptides in patients with tumors carrying the NSFP1-LRRC37A2 fusion. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Mistretta, Rankothgedera, Castillo, Rao, Holloway, Bhardwaj, El Noafal, Albarracin, El-Zein, Rezaei, Su, Akbani, Shao, Czerniecki, Karchin, Bedrosian and Gunaratne.)
Databáze:	MEDLINE
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