Quantitative engineering biology in the tumormicroenvironment

Abstract

Immunotherapy is a breakthrough in recent cancer therapy; however, in current clinical settings, responses to the current immunotherapy strategies, such as immune-checkpoint blockade and adoptive T cell transfer, remain poor. Therefore, elucidating the mechanisms underlying the non-responsiveness of cancer patients is a current focus in the field of cancer research. Among various factors, the tumor microenvironment is considered to be a promising research direction. The tumor microenvironment is a complex system and an essential player in the success of cancer immunotherapy. The tumor microenvironment is composed of tumor cells, immune cells, fibroblasts, extracellular matrix, blood vessels, and nutrients. To quantify the effects of the tumor microenvironment on cancer immunotherapy as well as reshape the tumor microenvironment to synergistically enhance the cancer immunotherapy, quantitative engineering biology can be employed. In this review, we will first introduce quantitative methods that measure parameters of the tumor microenvironment, such as mass cytometry by time-of-flight (CyTOF), multiplex imaging of tumor sections, single-cell RNA-seq. Specifically, CyTOF and multiplex imaging can provide the spatial information on tissue materials and the phenotype of different cells, which can be essential for predicting the response rate of cancer immunotherapy, whereas single-cell RNA-seq can give a more complete picture of the phenotypes of cells in tumors but without the spatial information. In addition, other quantitative methods that measure physical parameters of the tumor microenvironment, such as pH, tumor stiffness and oxygen level, can further help to elucidate the role of these factors in the spatial-temporal evolution of cell phenotypes and tissue materials in tumors. These technologies continue to provide quantitative understanding of the tumor microenvironment and fuel new ideas for engineering the tumor microenvironment. Furthermore, we will introduce the current, promising applications of engineering biology for reshaping the tumor microenvironment, such as immunotherapies based on chimeric antigen receptor T cells (CAR-T), T-cell receptor T cells (TCR-T), and dendritic-cell based tumor vaccines. Each engineering strategy has its own advantages and challenges, for example, CAR-T cells can target cells with specific surface proteins and do not require the co-stimulation process; however, they are currently limited to the target proteins for CAR-T. Furthermore, CAR-T therapy runs the risk of generating a cytokine storm. Conversely, TCR-T is safer, but the response rate is low without a deep understanding of complimentary suppressive pathways. Nevertheless, quantitative engineering biology is transforming research on tumor immunotherapy and new technologies are emerging to overcome the current barriers.