Cancer Neoantigens: Implications for Immune Response and Cancer Immunotherapy

Tumour specific splicing presents a large new class of splicing associated potential neoantigens

The ability of cancer cells to elicit an immune response depends on several factors, including their expression of neoantigens. A recent analysis by Gunnar Rätsch of the ETH Zurich, Department of Computer Science, Zurich, Switzerland and colleagues from the Cancer Genome Atlas Research Network reveals some clues on questions such as how many antigens tumour cells express or do different types of tumours express the same neoantigens. The investigators published their findings in the Cancer Cell.

Immunotherapy is currently a promising treatment for cancer patients. However, not all cancer types are suitable for this type of treatment. Among those that show potential benefit from immunotherapy, deriving suitable antigens for a targeted vaccine is a considerable challenge. Tumour specific splicing presents a large new class of splicing associated potential neoantigens that may affect the immune response and could be exploited in immunotherapy. 

The investigators performed a comprehensive analysis of alternative splicing across 32 cancer types (The Cancer Genome Atlas) from 8705 patients. The analysis detected alternative splicing events and tumour variants by re-analyzing RNA and whole-exome sequencing data.

Tumours have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations and identified additional trans-acting variants. 

Many tumours have thousands of alternative splicing events not detectable in normal samples. On average, the investigators identified approximately 930 exon-exon junctions ("neojunctions") in tumours not typically found in Genotype-Tissue expression (GTEx) normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumour samples, the investigators confirmed approximately 1.7 neojunction- and approximately 0.6 single nucleotide variant (SNV)-derived peptides per tumour sample that are also predicted major histocompatibility complex-I binders ("putative neoantigens").

By considering neojunction-derived, in addition to SNV-derived, peptides as potential antigens, the fraction of samples for which at least one putative neoantigen can be identified and confirmed by mass spectrometry proteomics increases from 30% to 75%.

In this study the authors considered many differences of alternative splicing in cancer compared with normal cells and suggest that these differences are characteristic for individual cancer types and could be used for the design of immunotherapeutic interventions, such as chimeric antigen receptor T cell therapy or personalised anti-cancer vaccines. 

 

Reference

Kahles A, Lehmann KV, Toussaint NC, et al. Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. Cancer Cell 2018; 34(2):211-224.e6. doi: 10.1016/j.ccell.2018.07.001.