Statistical Inference Methods to Identify Tumor Microenvironment Heterogeneity

Abstract

The tumor microenvironment (TME) is a dynamic ecosystem that is continually tested and shaped by the tumor cells. It protects the tumor cells from being attacked by the host immune system and facilitates tumor growth. Therefore, it is of significant interest to understand the cell- cell interplays within the TME to help demystify the mechanisms of immune evasion. However, current computational methods fail to reveal the whole picture of the cell-cell interactions since the activated cell functions in the cell are not fully captured. Several text mining models and factorization analysis methods have been developed to solve this problem; nevertheless, they require strong hidden assumptions that are not met in the context of molecular biology. The goal of this work is to explore a way to quantify and estimate the utility of upregulated functions (specific biological activities that a cell would perform) for cell differentiation and specialization, through which to understand and interpret the communications between cells in a causal relationship. To this end, I developed three aims and address them step by step: 1) scGEM is a nonparametric Bayesian model based on a Dirichlet process to identify correlated gene co- expressing modules within the cell subtypes. The gene modules identified by scGEM are expected to follow cell differentiation path and reflect cellular functions at a higher resolution than the current methods; 2) CRCAtlas uses scGEM to investigate gene modules of colorectal cancer and then employs a pharmacological computational method to locate the ligand receptor pairs that explain such correlations; 3) IOhub is introduced as one of the largest publicly curated databases for immuno-oncology research. By incorporating the gene modules from single cells, IOhub has the potential to discover new biomarkers to predict clinical response to immune checkpoint blockade. Overall, this dissertation contributes to the understanding of cancer immunology and the advancement of precision medicine