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Published on: September 20, 2017
APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy
Amélie Boichard1, Timothy V Pham2, Huwate Yeerna1
1Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, La Jolla, CA, USA.
Abstract:
Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression. Moreover, APOBEC-related mutagenesis correlated with immunotherapy response in a cohort of 99 patients with diverse cancers, and this correlation was independent of the tumor mutation burden (TMB). Combining APOBEC-related mutagenesis estimate and TMB resulted in greater predictive ability than either parameter alone. Based on these results, further investigation of APOBEC-related mutagenesis as a marker of response to anti-cancer checkpoint blockade is warranted.
Insights
APOBEC mutagenesis increases neo-antigen hydrophobicity, enhancing anti-cancer immunity. This mechanism predicts immunotherapy response, independent of tumor mutation burden, offering a new biomarker for checkpoint blockade therapy.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Tumor-associated neo-antigens are crucial for immune recognition of cancer cells.
- High tumor mutation burden can paradoxically induce immune tolerance.
- PD-L1/PD-1 checkpoint immunotherapy shows promise but requires better predictive markers.
Purpose of the Study:
- To investigate the role of APOBEC-related mutagenesis in neo-antigen immunogenicity.
- To determine if APOBEC-related mutagenesis predicts response to PD-L1/PD-1 checkpoint immunotherapy.
- To assess the combined predictive value of APOBEC mutagenesis and tumor mutation burden (TMB).
Main Methods:
- In silico computation of neo-peptide hydrophobicity.
- Analysis of the TCGA pan-cancer cohort for APOBEC mutagenesis and immune markers.
- Correlation analysis of APOBEC mutagenesis with immunotherapy response in a patient cohort.
- Evaluation of TMB and APOBEC mutagenesis as combined predictive markers.
Main Results:
- APOBEC-related mutagenesis increases neo-peptide hydrophobicity, a marker of immunogenicity.
- APOBEC mutagenesis correlates with immune marker expression in pan-cancer data.
- APOBEC mutagenesis predicts immunotherapy response independently of TMB.
- Combined APOBEC mutagenesis and TMB offer superior predictive ability for immunotherapy response.
Conclusions:
- APOBEC-related mutagenesis enhances neo-antigen immunogenicity and predicts immunotherapy response.
- APOBEC mutagenesis is a promising biomarker for anti-cancer checkpoint blockade therapy.
- Further investigation into APOBEC mutagenesis as a predictive marker is warranted.
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