Immune escape at the onset of human colorectal cancer

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early stage cancers are frequently detected and surgically removed. Here, we examine the role of the immune response in tumor initiation by studying tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology, and multi-region neoantigen prediction. Observed changes in antigenic intra-tumor heterogeneity (aITH), the tumor ecology, and spatial patterns of both cell associations and gene expression are consistent with simulations where immunogenic adenomas do not progress to CRC because they are under immune control. Conversely, adenomas that progress initially avoid detection through low immunogenicity, but gradually construct an immunosuppressive niche isolated from CD8+ cytotoxic T cells, thereby evading immune elimination and allowing for an increase in neoantigen burden. Both modeling and data indicate that immune blockade (e.g. PD-L1 expression) plays a secondary role to immune suppression in tumor initiation or progression. These results suggest that re-engineering the immunosuppressive niche may prove to be a most effective immunotherapy in CRC.