RNA Dysregulation: An Expanding Source of Cancer Immunotherapy Targets

Yang Pan; Kathryn E Kadash-Edmondson; Robert Wang; John Phillips; Song Liu; Antoni Ribas; Richard Aplenc; Owen N Witte; Yi Xing

doi:10.1016/j.tips.2021.01.006

RNA Dysregulation: An Expanding Source of Cancer Immunotherapy Targets

Trends Pharmacol Sci. 2021 Apr;42(4):268-282. doi: 10.1016/j.tips.2021.01.006.

Authors

Yang Pan¹, Kathryn E Kadash-Edmondson², Robert Wang³, John Phillips⁴, Song Liu⁵, Antoni Ribas⁶, Richard Aplenc⁷, Owen N Witte⁸, Yi Xing⁹

Affiliations

¹ Bioinformatics Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
² Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁶ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: xingyi@email.chop.edu.

Abstract

Cancer transcriptomes frequently exhibit RNA dysregulation. As the resulting aberrant transcripts may be translated into cancer-specific proteins, there is growing interest in exploiting RNA dysregulation as a source of tumor antigens (TAs) and thus novel immunotherapy targets. Recent advances in high-throughput technologies and rapid accumulation of multiomic cancer profiling data in public repositories have provided opportunities to systematically characterize RNA dysregulation in cancer and identify antigen targets for immunotherapy. However, given the complexity of cancer transcriptomes and proteomes, important conceptual and technological challenges exist. Here, we highlight the expanding repertoire of TAs arising from RNA dysregulation and introduce multiomic and big data strategies for identifying optimal immunotherapy targets. We discuss extant barriers for translating these targets into effective therapies as well as the implications for future research.

Keywords: CAR-T; RNA processing; RNA-seq; TCR; cancer immunotherapy; proteogenomics; proteome; transcriptome; tumor antigen.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Humans
Immunotherapy
Neoplasms* / genetics
Neoplasms* / therapy
Proteome
RNA* / genetics
Transcriptome

Substances

Proteome
RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding