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M.F. Mohd Omar
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-058 - Mutational Features Associated with Immunoreactivity in Non-Small Cell Lung Cancer (ID 5315)
14:30 - 14:30 | Author(s): M.F. Mohd Omar
- Abstract
Background:
Recent reports convey that the abundance and patterns of DNA mutational features in human cancers could modulate their antigenicity and sensitivity to immune checkpoint blockade. We thus sought to comprehensively characterise the immunogenomic landscape of NSCLC.
Methods:
We used publicly-available molecular (DNA mutation and RNA expression profiles) and clinical data of 658 NSCLC patients from The Cancer Genome Atlas project. HLA-type was inferred using POLYSOLVER, and we identified neoantigens with patient-specific HLA-binding affinity of IC50<500nm using NetMHC. The relative tumour infiltration by 22 immune cell types was enumerated using CIBERSORT. Finally, we developed and applied MUTPROFILER, a computational approach for mutational signature analysis capable of decrypting sequence alterations across 96 trinucleotide contexts and indels of varying lengths.
Results:
This analysis recapitulated a pervasive and prominent association between neoantigen levels and the molecular smoking signature (that is characterised by C:G>A:T transversions; Spearman ρ=0.78, P=1.37×10[-69]), and identified several novel and powerful immunogenetic associations in NSCLC. For instance, the proportion of activated natural killer (NK) cells was greater in tumours which showed a higher abundance of 1-3bp insertion/deletions (indels; ρ=0.23, P=1.34×10[-9]). Furthermore, small (1bp) indels were associated with increased expression of markers of immune cytolytic activity, including TNFA (TNFα; ρ=0.30, P=4.77×10[-15]), GZMA (ρ=0.21, P=4.92×10[-8]) and PRF1 (ρ=0.15, P=1.84×10[-4]). Fourteen trinucleotide alterations, including GCA>GTA, TCG>TAG and TCG>TGG, were more strongly correlated with PDCD1LG2 (PD-L2) expression compared to small indels (q<5×10[-8], Fisher’s Z-transformation). Interestingly, the number of small frameshifting indels was associated with downregulation of the antigen-presenting machinery (APM) such as TAP1 (ρ=–0.22, P=7.93×10[-9]) and TAP2 (ρ=–0.23, P=1.69×10[-9]), suggesting a potential immunoediting mechanism by which NSCLC tumours co-opt APM pathways to prevent neoantigen-recognition. Finally, by analysing the mutational signatures of the AID/APOBEC family, which has important roles in adaptive and innate immunity, we identified a potential novel mutagenic contribution of APOBEC3H, whose expression levels was associated with a pattern of C>A (ρ=0.18, P=4.76×10[-6]) and C>G (ρ=0.14, P=3.67×10[-4]) within TC motifs (with the mutated base underlined).
Conclusion:
Our study portrays an atlas of immunogenetic features in NSCLC. The results sheds light on the dynamics of tumour-immune cell interactions which are likely to form the driving force behind the clinical activity of novel immunologic strategies, and may lead to new biomarkers and targets for cancer immunotherapy.
