Coevolution of epithelium and immune response in colorectal cancer: comprehensive longitudinal analysis and manipulation of crosstalk leading to exhausted responses in dedicated mouse models.

Overall MSS colorectal cancer (CRC) is considered a cold tumor, nonresponsive
to immunotherapy, in contrast to MSI CRC. We observe all MSS
are dysfunctional at the level of T cell responses, but with heterogeneous
mechanisms with some having cytotoxic CD8 T cells stuck in stroma,
whereas in others T cells are in tolerogenic/pro-tumorigenic states as Treg
and Th17, or some are entirely cold. Our extensively mapped out
differences in immunogenicity/immune evasive interactions in CRC are
likely caused by co-evolution of epithelial transformations with their
microenvironment. To understand CRC's evolutionary consequences for
immunogenicity, we will use a set of unique mouse models matching patient
heterogeneity to longitudinally follow tumor establishment,
immunogenicity and manipulate immune evasive interactions
observed in human CRC. These results will provide first insight in how
immune-ignored tumors are established, possible therapeutic manipulations
and a toolkit to phenotype and manipulate immunogenicity in a large variety
of models for therapies.