Abstract PR008: Immunosuppressive niche engineering at the onset of human colorectal cancer

Abstract

Abstract 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 demonstrate a key role for 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 data, and multi-region exome sequencing and neoantigen prediction in a total of 62 patient samples. Modelling indicates there are several potential routes to malignancy, each of which uniquely sculpts tumor ecology and intra-tumor antigenic heterogeneity (aITH). In patient samples, the immune microenvironment was characterized using the spatial distribution of 17 markers across registered whole-slide images, as well as patterns of intra-lesion aITH measured using multi-region exome sequencing and neoantigen prediction. The patient data were best described by a model where adenomas that become immunogenic early on do not progress to CRC because they are under immune control; progression therefore proceeds in adenomas with low immunogenicity. In these tumors, immune suppression is initially low, but gradually an immunosuppressive niche that is depleted in CD8+ cytotoxic T cells expands. There was little evidence for immune blockade (PD-L1 expression) in tumor initiation or progression. These results suggest that re-engineering the immunosuppressive niche may prove to be an effective immunotherapy in CRC. Citation Format: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson. Immunosuppressive niche engineering at the onset of human colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR008.