PT - JOURNAL ARTICLE AU - Mirjana Efremova AU - Victoria Klepsch AU - Pornpimol Charoentong AU - Francesca Finotello AU - Dietmar Rieder AU - Hubert Hackl AU - Natascha Hermann-Kleiter AU - Gottfried Baier AU - Anne Krogsdam AU - Zlatko Trajanoski TI - Targeting the PD-1/PD-L1 pathway potentiates immunoediting to counterbalance neutral evolution in a mouse model of colorectal cancer AID - 10.1101/099747 DP - 2017 Jan 01 TA - bioRxiv PG - 099747 4099 - http://biorxiv.org/content/early/2017/01/11/099747.short 4100 - http://biorxiv.org/content/early/2017/01/11/099747.full AB - Background The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the developing tumor by editing the cancer genome. However, to what extent immunoediting is shaping the cancer genome in common malignancies is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating immunoediting remains largely unexplored.Results Here we employed a mouse model of colorectal cancer (CRC), next-generation sequencing, and computational analyses to elucidate the impact of evolutionary and immune-related forces on editing the tumor. We first carried out genomic and transcriptomic analyses of a widely-used model, MC38 cell line and show that this is a valid model for hypermutated and microsatellite-unstable CRC. Analyses of the data from longitudinal samples of wild type and immunodeficient RAG1 knockout mice transplanted with MC38 cells revealed that upregulation of checkpoint molecules and infiltration of Tregs are the major tumor escape mechanisms. Strikingly, the impact of neutral evolution on sculpting the tumor outweighed immunoediting by T cell dependent and T cell independent mechanisms in the progressing tumors. We also show that targeting the PD-1/PD-L1 pathway potentiated immunoediting and rendered tumors more homogeneous.Conclusions In summary, our study demonstrates that neutral evolution is the major force that sculpts the tumor during progression, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in this model. The results have important implication for basic research studies on the mechanisms of resistance to checkpoint blockade and for clinical translation.