Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression

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PROJECT SUMMARY/ABSTRACT Project 3: Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression The pre-cancer-to-cancer transition is a critical juncture in colorectal cancer (CRC) biology that has clinical value in prevention and surveillance. This transition is characterized by an “evolutionary arms race” where the body’s immune system seeks to eliminate the tumor while the tumor cells evolve mechanisms to suppress and evade the immune system. The small number of human pre-precancers that transition into cancer precludes effective predictive modeling of critical genetic and microenvironmental factors that drive these alterations. Herein, we will leverage regional intratumoral heterogeneity, due to asynchronicity of evolution, with spatially resolved profiling technologies on human tumor specimens to build trajectories of pre-cancer transition into malignancy. We will model two pathways of pre-cancer transitions, the conventional pathway driven by mutations in the WNT pathway and the serrated pathway characterized by an immunogenic microenvironment. Our previous pre- cancer atlas describes a dichotomy between stemness in tumor cells and cytotoxic T cells in the microenvironment between these two pathways. Thus, we hypothesize that pre-cancers gain stemness to enable epithelial mechanisms to suppress a cytotoxic immune environment, resulting in malignant evolution. In Aim 1, we will use spatially resolved DNA sequencing to map genetic evolution of pre-cancer cells with selective pressures conferred by neoantigen-specific adaptive immunity. In Aim 2, we will use integrative spatial multi- omics to interrogate tumor mechanisms to modulate immune cell communication networks during progression. By combining novel technologies with data-driven systems modeling, we will shed light on the complex interplay between human tumors and their microenvironment that shape their transition trajectories into malignancy.