Cancer stemness, intratumoral heterogeneity, and immune response across cancers

Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9020-9029. doi: 10.1073/pnas.1818210116. Epub 2019 Apr 17.


Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype ("stemness") on the immunological properties of cancer has not been systematically explored. Using gene-expression-based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and immune suppression across cancers.

Keywords: antitumor immunity; cancer stemness; intratumoral heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Databases, Genetic
  • Gene Expression / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Genomics / methods
  • Humans
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Transcriptome / genetics
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology