IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

Pan, Yang; Lee, Alexander; Yang, Haiou; Wang, Yuan‐Yuan; Yang, Xu; Kadash-Edmondson, Kathryn E.; Phillips, John W.; Champhekar, Ameya S.; Puig, Cristina; Ribas, Antoni; Witte, Owen N.; Prins, Robert M.; Xing, Yi

doi:10.1101/843268

Cited by 12 publications

(17 citation statements)

References 38 publications

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“…Previous studies have established the importance of alternative and aberrant splicing in cancer prognosis ( 6–11 ) and have begun to explore its potential relevance in cancer immunotherapy ( 15 , 23 , 45 ). In this study, we explore ‘novel’ exon–exon junctions used among cancers with respect to a broad collection of normal tissue and cell types.…”

Section: Discussionmentioning

confidence: 99%

“…This study also predicted alternative splicing neoepitopes via this comparison, and validated several of these neoepitopes shared between multiple patients with the intracellular proteomics data available for select ovarian and breast cancer TCGA donors in the Clinical Proteomic Tumor Analysis Consortium dataset ( 15 ). More recently, another study has leveraged TCGA and GTEx, as well as cell line data, to discover and validate neoepitopes derived from alternative splicing ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Putatively cancer-specific exon–exon junctions are shared across patients and present in developmental and other non-cancer cells

et al. 2020

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This study probes the distribution of putatively cancer-specific junctions across a broad set of publicly available non-cancer human RNA sequencing (RNA-seq) datasets. We compared cancer and non-cancer RNA-seq data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) Project and the Sequence Read Archive. We found that (i) averaging across cancer types, 80.6% of exon–exon junctions thought to be cancer-specific based on comparison with tissue-matched samples (σ = 13.0%) are in fact present in other adult non-cancer tissues throughout the body; (ii) 30.8% of junctions not present in any GTEx or TCGA normal tissues are shared by multiple samples within at least one cancer type cohort, and 87.4% of these distinguish between different cancer types; and (iii) many of these junctions not found in GTEx or TCGA normal tissues (15.4% on average, σ = 2.4%) are also found in embryological and other developmentally associated cells. These findings refine the meaning of RNA splicing event novelty, particularly with respect to the human neoepitope repertoire. Ultimately, cancer-specific exon–exon junctions may have a substantial causal relationship with the biology of disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Putatively cancer-specific exon–exon junctions are shared across patients and present in developmental and other non-cancer cells

et al. 2020

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“…Future work should establish standardized transcriptome references for different types of RNA dysregulation and patient populations. For example, Genotype-Tissue Expression (GTEx) is a commonly used reference database of normal transcriptome profiles [21,88], but the GTEx RNA-seq data are exclusively derived from adult tissues [59]. Transcriptome references for normal pediatric tissues would be instrumental for TA discovery in pediatric cancers.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

RNA Dysregulation: An Expanding Source of Cancer Immunotherapy Targets

Pan

Kadash-Edmondson

Wang

et al. 2021

Trends in Pharmacological Sciences

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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.

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“…In the case of targeted T-cell therapies, this underscores the importance of focusing on multiple neoantigens shared by the entire tumor to prevent antigenic evolution. 32,33 Neojunctions can generate immunogenic antigens, [34][35][36]38 and to that end, we explored the ITH of public neojunctions by filtering for neojunction reads across multiple samples from the same tumor (Figure 3A). RNA-seq data derived from multiple intratumor samples in prostate, 39 liver, [40][41][42][43] colon, 40,44 stomach, 40 kidney, 40 and lung 45,46 were analyzed to investigate whether public neojunctions are present across the tumor landscape in various cancer types (Figures S1).…”

Section: Neojunctions Exhibit Intratumor Heterogeneitymentioning

confidence: 99%

“…26,27 These cancer-specific splicing events, otherwise known as neojunctions, are prevalent in cancer cells and capable of generating novel TSAs that potentiate CD8 + T-cell-mediated expansion and responses in select cancer types. 26,28,30,[34][35][36][37][38] Nevertheless, to date, no study has examined the conservation of neojunctions across whole tumors, and therefore, those identified neojunction-derived targets face similar therapeutic barriers due to ITH.…”

Section: Introductionmentioning

confidence: 99%

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens

Kwok,

Stevers,

Nejo

et al. 2023

Preprint

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T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide. We identified CD8+ T-cell clones specific for neoantigens derived from tumor-wide and conserved neojunctions in GNAS and RPL22, respectively. TCR-engineered CD8+ T-cells targeting these mutations conferred neoantigen-specific tumor cell eradication. Furthermore, we revealed that cancer-specific dysregulation in splicing factor expression leads to recurrent neojunction expression. Together, these data reveal that a subset of neojunctions are both intratumorally conserved and public, providing the molecular basis for novel T-cell-based immunotherapies that address intratumoral heterogeneity.

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IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

Cited by 12 publications

References 38 publications

Putatively cancer-specific exon–exon junctions are shared across patients and present in developmental and other non-cancer cells

Putatively cancer-specific exon–exon junctions are shared across patients and present in developmental and other non-cancer cells

RNA Dysregulation: An Expanding Source of Cancer Immunotherapy Targets

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens

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