Efremova et al. used the MC38 (hypermutated, immunogenic) and CT26 (less mutated, less immunogenic) tumor models to quantitatively evaluate the cancer immunoediting hypothesis and the role of checkpoint blockade in immunoediting. They observed that normal tumor progression is dominated by neutral evolution, in which mutations accumulate independently of their impact on progression or immunogenicity. Checkpoint blockade induces selective pressure by the immune system, which leads to more pronounced immunoediting and results in more homogenous tumors.
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.
Author Info: (1) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (2) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruc
Author Info: (1) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (2) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (3) Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria. (4) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (5) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (6) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (7) Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria. (8) TRON -Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany. (9) Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria. (10) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. anne.krogsdam@i-med.ac.at. (11) Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. zlatko.trajanoski@i-med.ac.at.
