APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy.

Cancer Immunotherapy

Cancer Immunotherapy (NCI / Duncan Comprehensive Cancer Center at Baylor College of Medicine)

Boichard A, Pham TV, Yeerna H, Goodman A, Tamayo P, Lippman S, Frampton GM, Tsigelny IF, Kurzrock R.

OncoImmunology

December 24, 2018

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 silicocomputation 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.

Program:
CTD²
Last updated: April 29, 2019