RNA Dysregulation: An Expanding Source of Cancer Immunotherapy Targets

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. RNA Dysregulation as a Source of Cancer Immunotherapy Targets Transcriptomic and proteomic outputs of human cells are controlled by multiple RNA-level regulatory processes. Mechanisms, such as pre-mRNA alternative splicing (AS, see Glossary) and RNA editing, can generate multiple protein isoforms from a single gene, greatly expanding the coding capacity and protein repertoire of human cells. Cancer cells exhibit widespread abnormalities in RNA processing, including driver alterations that functionally contribute to cancer development and progression [1,2]. Through prevalent RNA dysregulation, cancer cells can express a distinct set of transcripts and proteins, some of which may represent therapeutic targets.

A widespread length-dependent splicing dysregulation in cancer

“…Collectively, this study reveals a general rule for AS dysregulation in cancers, provides a simple and practical route for cancer stratification with AS, and uncovers the potential underlying mechanisms. Because the splicing dysregulation was recently found to associate with cancer immunotherapy and drug assistance (63,64), our study provides valuable information for cancer prediction with clinical implications.…”

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing – Review

“…Additionally, big data approaches are used to analyze multi-omics data from cancer cells. Such knowledge allows translating experimental results into new, more efficient therapies with an unprecedented power [64].…”

Probing Isoform Switching Events in Various Cancer Types: Lessons From Pan-Cancer Studies

“…Understanding the relationship between the patterns of alternative splicing and cancer could help to gain insights into the origins of cancer formation and elicit potential therapies targeting cancer-specific protein isoforms ( Le et al, 2015 ; Jaudon et al, 2020 ; Fuchs et al, 2021 ; Pan et al, 2021 ). Aberrant splicing in cancer can be caused by mutations at consensus sequences (5′ splice site, 3’ splice site and branch point), cis- regulatory elements (ESE, ESS, ISS, ISE), or mutations and expression changes in genes encoding splicing regulatory proteins.…”