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Alternative mRNA splicing in cancer immunotherapy

Nature Reviews Immunology volume 19, pages 675–687 (2019)Cite this article

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Abstract

Immunotherapies are yielding effective treatments for several previously untreatable cancers. Still, the identification of suitable antigens specific to the tumour that can be targets for cancer vaccines and T cell therapies is a challenge. Alternative processing of mRNA, a phenomenon that has been shown to alter the proteomic diversity of many cancers, may offer the potential of a broadened target space. Here, we discuss the promise of analysing mRNA processing events in cancer cells, with an emphasis on mRNA splicing, for the identification of potential new targets for cancer immunotherapy. Further, we highlight the challenges that must be overcome for this new avenue to have clinical applicability.

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Fig. 1: Alternative splicing and immunotherapy.
Fig. 2: Schematic illustration of the development of potential immunotherapies targeting mRNA processing-derived neoantigens.
Fig. 3: Potential mechanism of tumour escape from immunotherapy.

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Acknowledgements

Preparation of this review was supported by an endowment provided by the Raymond and Beverly Sackler Foundation, the Parker Institute for Cancer Immunotherapy and the National Cancer Institute (grant 1U54 CA199090-01).

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Authors and Affiliations

  1. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Luke Frankiw & David Baltimore

  2. Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Guideng Li

  3. Suzhou Institute of Systems Medicine, Suzhou, China

    Guideng Li

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  1. Luke Frankiw
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  2. David Baltimore
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The authors contributed equally to all aspects of the article.

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Glossary

Major histocompatibility complex

(MHC). A set of genes that code for cell surface proteins (most notably the MHC class I and class II glycoproteins) that are responsible for presenting antigens to lymphocytes.

Adoptive cell therapy

A type of immunotherapy approach that uses antigen-specific T cells to treat patients with chronic viral infections or various malignancies.

Non-synonymous mutation

A nucleotide mutation that changes the amino acid sequence of a protein.

Neoantigens

Newly formed antigens that have not been previously recognized by the immune system.

Cancer germline antigens

Antigens that are normally exclusively expressed in germline cells but have aberrant expression in tumours, such as NY-ESO-1.

Tumour mutational burden

(TMB). Also referred to as the tumour mutational load, this is a measurement of mutations carried by tumour tissue taken from a patient.

Tumour-specific antigens

(TSAs). Antigens that are exclusively presented by tumour cells but not by any other cells.

RNA editing

A molecular process resulting in alteration of the RNA sequence before translating to protein.

Alternative polyadenylation

(APA). An RNA-processing event that generates distinct 3ʹ termini on mRNAs and other RNA polymerase II transcripts.

Alternative splicing

A regulated process during gene expression that results in a single gene coding for multiple proteins.

Intron retention

A form of alternative splicing that results in inclusion of introns in the final protein product.

Spliceosome

The multi-megadalton ribonucleoprotein complex responsible for removing introns from pre-mRNA sequences.

The Cancer Genome Atlas

(TCGA). The world’s largest and richest collection of genomic data.

Nonsense-mediated decay

A translation-coupled mechanism that degrades mRNAs harbouring premature translation-termination codons.

Splice-site-creating mutations

(SCMs). Genomic mutations that induce splice-site creation. Often mis-annotated as missense and silent mutations.

Clinical Proteomic Tumor Analysis Consortium

(CPTAC). The first large-scale project that produced proteomics data sets from the mass spectrometric interrogation of tumour samples previously studied by The Cancer Genome Atlas programme.

Neojunctions

Novel exon–exon junctions found in tumour samples that are not typically found in healthy tissue.

Indels

Insertion or deletion of nucleotides into genomic DNA, less than 1 kb in length.

Checkpoint inhibitors

(CPIs). Types of drug that block the inhibitory checkpoint molecules.

Crossreactivity

The recognition of two or more peptide–major histocompatibility complex complexes by a T cell receptor.

Immune Epitope Database

(IEDB). A database containing detailed information for more than 100,000 unique immune epitopes related to infectious and immune-mediated diseases.

Trogocytosis

A biological process where interacting cells share membrane and membrane-associated proteins.

Chimeric antigen receptor

(CAR). Recombinant receptor protein that has been engineered to direct T cells to target a specific protein on malignant cells.

Loss of heterozygosity

A common somatic genome event that results in loss of the entire gene and the surrounding chromosomal region.

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Frankiw, L., Baltimore, D. & Li, G. Alternative mRNA splicing in cancer immunotherapy. Nat Rev Immunol 19, 675–687 (2019). https://doi.org/10.1038/s41577-019-0195-7

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