Systems glycobiology for discovering drug targets, biomarkers, and rational designs for glyco-immunotherapy

Austin W. T. Chiang, Hratch M. Baghdassarian, Benjamin P. Kellman, Bokan Bao, James T. Sorrentino, Chenguang Liang, Chih-Chung Kuo, Helen O. Masson, Nathan E. Lewis

Cancer immunotherapy has revolutionized treatment and led to an unprecedented wave of immuno-oncology research during the past two decades. In 2018, two pioneer immunotherapy innovators, Tasuku Honjo and James P. Allison, were awarded the Nobel Prize for their landmark cancer immunotherapy work regarding "cancer therapy by inhibition of negative immune regulation" -CTLA4 and PD-1 immune checkpoints. However, the challenge in the coming decade is to develop cancer immunotherapies that can more consistently treat various patients and cancer types. Overcoming this challenge requires a systemic understanding of the underlying interactions between immune cells, tumor cells, and immunotherapeutics. The role of aberrant glycosylation in this process, and how it influences tumor immunity and immunotherapy is beginning to emerge. Herein, we review current knowledge of miRNA-mediated regulatory mechanisms of glycosylation machinery, and how these carbohydrate moieties impact immune cell and tumor cell interactions. We discuss these insights in the context of clinical findings and provide an outlook on modulating the regulation of glycosylation to offer new therapeutic opportunities. Finally, in the coming age of systems glycobiology, we highlight how emerging technologies in systems glycobiology are enabling deeper insights into cancer immuno-oncology, helping identify novel drug targets and key biomarkers of cancer, and facilitating the rational design of glyco-immunotherapies. These hold great promise clinically in the immuno-oncology field.