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Nat Commun. 2018 Jan 2;9(1):32. doi: 10.1038/s41467-017-02424-0.

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

Author information

1
Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.
2
Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria.
3
TRON -Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany.
4
Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. anne.krogsdam@i-med.ac.at.
5
Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. zlatko.trajanoski@i-med.ac.at.

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.

PMID:
29296022
PMCID:
PMC5750210
DOI:
10.1038/s41467-017-02424-0
[Indexed for MEDLINE]
Free PMC Article

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