Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited by Douglas Hanahan, Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland, and approved March 22, 2019 (received for review October 22, 2018)
Significance
The exclusion of immune cells from the tumor microenvironment has been associated with poor prognosis in the majority of cancers. We report that when considering 21 solid cancer types, immune cell exclusion is widely associated with the presence of a stem cell-like phenotype in tumors (“stemness”). Stemness positively correlates with higher intratumoral heterogeneity, possibly by protecting antigenic clones from elimination by the immune system. The activation of a stemness program appears to limit antitumor immune responses via tumor cell-intrinsic silencing of endogenous retrovirus expression, repression of type I interferon signaling, and up-regulation of immunosuppressive checkpoints. Our work suggests that targeting the stemness phenotype in cancer will promote T cell infiltration and render tumors more responsive to immune control.
Abstract
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.
Footnotes
↵1A. Miranda. and P.T.H. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: bnelson{at}bccrc.ca.
Author contributions: A. Miranda, P.T.H., and B.H.N. designed research; A. Miranda and P.T.H. performed research; E.B., A. Mezheyeuski, J.B., P.M., and A.d.R. contributed new reagents/analytic tools; A. Miranda, P.T.H., A.W.Z., S.P., and B.H.N. analyzed data; B.H.N. conducted study supervision; and A. Miranda, P.T.H., and B.H.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818210116/-/DCSupplemental.
Published under the PNAS license.
Cancer stemness, intratumoral heterogeneity, and immune response across cancers
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