Cross-domain feature disentanglement for interpretable modeling of tumor microenvironment impact on drug response

High-throughput screening technology has facilitated the generation of large-scale drug responses across hundreds of cancer cell lines. However, there exists significant discrepancy between in vitro cell lines and actual tumors in vivo in terms of their response to drug treatments, because of tumors comprise of complex cellular compositions and histopathology structure, known as tumor microenvironment (TME), which greatly influences the drug cytotoxicity against tumor cells. To date, no study has focused on modeling the impact of the TME on clinical drug response. This paper proposed a domain adaptation network for feature disentanglement to separate representations of cancer cells and TME of a tumor in patients. Two denoising autoencoders were separately used to extract features from cell lines (source domain) and tumors (target domain) for partial domain alignment and feature decoupling. The specific encoder was enforced to extract information only about TME. Moreover, to ensure generalizability to novel drugs, we applied a graph attention network to learn the latent representation of drugs, allowing us to linearly model the drug perturbation on cellular state in latent space. We calibrated our model on a benchmark dataset and demonstrated its superior performance in predicting clinical drug response and dissecting the influence of the TME on drug efficacy.