Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

Amy A. Lo*, Andrew Wallace, Daniel Oreper, Nicolas Lounsbury, Charles Havnar, Ximo Pechuan-Jorge, Thomas D. Wu, Richard Bourgon, Ryan Jones, Katrina Krogh, Guang Yu Yang, Oliver A. Zill*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Background Individualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types. Methods We combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting. Results Branching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases. Conclusions We show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.

Original languageEnglish (US)
Article numbere003001
JournalJournal for immunotherapy of cancer
Issue number10
StatePublished - Oct 1 2021


  • antigen-mediated
  • antigens
  • biomarkers
  • clonal selection
  • computational biology
  • neoplasm
  • tumor
  • urinary bladder neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Immunology and Allergy
  • Pharmacology
  • Immunology


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