Immunoengineering can overcome the glycocalyx armour of cancer cells

• Published in: Nature materials Vol. 23; no. 3; pp. 429 - 438
• Main Authors: Park, Sangwoo, Colville, Marshall J., Paek, Justin H., Shurer, Carolyn R., Singh, Arun, Secor, Erica J., Sailer, Cooper J., Huang, Ling-Ting, Kuo, Joe Chin-Hun, Goudge, Marc C., Su, Jin, Kim, Minsoo, DeLisa, Matthew P., Neelamegham, Sriram, Lammerding, Jan, Zipfel, Warren R., Fischbach, Claudia, Reesink, Heidi L., Paszek, Matthew J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2024; Nature Publishing Group
• Subjects: 132/124; 631/250/251; 631/57/2282; Antigens; Armor; Biomaterials; Cancer; Chemistry and Materials Science; Condensed Matter Physics; Cytotoxicity; Editing; Enzymes; Immune system; Lymphocytes; Materials Science; Mucins; Nanotechnology; Optical and Electronic Materials; Physical properties; Polymers; Receptors; Tethering; Thickness; Toxicity
• ISSN: 1476-1122; 1476-4660; 1476-4660
• DOI: 10.1038/s41563-024-01808-0

Cancer cell glycocalyx is a major line of defence against immune surveillance. However, how specific physical properties of the glycocalyx are regulated on a molecular level, contribute to immune evasion and may be overcome through immunoengineering must be resolved. Here we report how cancer-associated mucins and their glycosylation contribute to the nanoscale material thickness of the glycocalyx and consequently modulate the functional interactions with cytotoxic immune cells. Natural-killer-cell-mediated cytotoxicity is inversely correlated with the glycocalyx thickness of the target cells. Changes in glycocalyx thickness of approximately 10 nm can alter the susceptibility to immune cell attack. Enhanced stimulation of natural killer and T cells through equipment with chimeric antigen receptors can improve the cytotoxicity against mucin-bearing target cells. Alternatively, cytotoxicity can be enhanced through engineering effector cells to display glycocalyx-editing enzymes, including mucinases and sialidases. Together, our results motivate the development of immunoengineering strategies that overcome the glycocalyx armour of cancer cells.
A nanoscale polymer layer formed by mucins at the surface of tumour cells protects them against immune cell attack. This shield can be circumvented through immune cell engineering, using chimeric antigen receptors to stimulate natural killer and T cells or by tethering glycocalyx-editing enzymes to immune cells.