Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

Mirjana Efremova, Dietmar Rieder, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Hubert Hackl, Natascha Hermann-Kleiter, Martin Löwer, Gottfried Baier, Anne Krogsdam () and Zlatko Trajanoski ()
Additional contact information
Mirjana Efremova: Medical University of Innsbruck
Dietmar Rieder: Medical University of Innsbruck
Victoria Klepsch: Medical University of Innsbruck
Pornpimol Charoentong: Medical University of Innsbruck
Francesca Finotello: Medical University of Innsbruck
Hubert Hackl: Medical University of Innsbruck
Natascha Hermann-Kleiter: Medical University of Innsbruck
Martin Löwer: TRON –Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH
Gottfried Baier: Medical University of Innsbruck
Anne Krogsdam: Medical University of Innsbruck
Zlatko Trajanoski: Medical University of Innsbruck

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates immunoediting. The immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-017-02424-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02424-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-02424-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().