Immunogenomic Landscape Contributes to Hyperprogressive Disease after Anti-PD-1 Immunotherapy for Cancer

Donghai Xiong, Yian Wang, Arun K. Singavi, Alexander C. Mackinnon, Ben George, Ming You

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


Although PD-1-blocking immunotherapies demonstrate significant therapeutic promise, a subset of the patients could develop hyperprogressive disease (HPD) with accelerated tumor growth after anti-PD1 immunotherapy. To elucidate the underlying mechanisms, we compared the mutational and transcriptional landscapes between the pre- and post-therapy tumors of two patients developing HPD after anti-PD-1 immunotherapy. In post-therapy HPD tumors, somatic mutations were found in known cancer genes, including tumor suppressor genes such as TSC2 and VHL, along with transcriptional upregulation of oncogenic pathways, including IGF-1, ERK/MAPK, PI3K/AKT, and TGF-β. We found that post-therapy HPD tumors were less immunogenic than pre-therapy tumors, concurrent with an increased presence of ILC3 cells, a subset of innate lymphoid cells. We also developed a gene expression signature predictive of HPD. In summary, we identified the genomics and immune features associated with HPD, which may help identify patients at risk of adverse clinical outcome after anti-PD-1 immunotherapy.

Original languageEnglish (US)
Pages (from-to)258-277
Number of pages20
StatePublished - Nov 30 2018


  • )
  • Biotechnology
  • Cell Biology
  • Immunology (186131996Physiology
  • Omics
  • Physiology (170590663/189723279

ASJC Scopus subject areas

  • General


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