Targeting the PD-1/PD-L1 pathway potentiates immunoediting and changes the dynamics of neutral evolution in a mouse model of colorectal cancer

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 the genome. However, to what extent immunoediting is shaping the cancer genome is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating immunoediting remains largely unexplored. Here we elucidated the impact of evolutionary and immune-related forces on editing the tumor in a mouse model of colorectal cancer (CRC). We first show that MC38 cell line is a valid model for hypermutated and microsatellite-unstable (MSI) CRC. Analyses of 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. Targeting the PD-1/PD-L1 pathway potentiated immunoediting and rendered tumors more homogeneous in the MC38 model. The immunoediting effects were less pronounced in a nonhypermutated/MSI- model CT26. Our study demonstrates that neutral evolution is the major force that sculpts the tumor, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in a hypermutated/MSI model of CRC.