(534c) Chemical Biology Tools for Identification of Siglec Ligands in Cancer

Cancer immunotherapies, including checkpoint blockade antibodies, represent a breakthrough in cancer treatment with long-term remission observed in select patients. Unfortunately, many tumors remain unresponsive to existing immunotherapies, creating an urgent need for mechanistic studies of additional immune checkpoints that drive cancer progression. Recent evidence suggests that upregulation of select glycoproteins modified with the sialic acid monosaccharide allow tumors to resist treatment by engaging a family of inhibitory receptors called Siglecs on immune cells. However, the molecular identities of Siglec ligands remain poorly understood, preventing therapeutic targeting of these emerging immune checkpoints. I hypothesize that each of the 8 inhibitory human Siglecs bind a discrete, non-overlapping set of glycopeptide ligands, representing a “Siglec code” for immune suppression. My work seeks to decipher this code by defining the molecular identities of Siglec ligands and translate these discoveries into development of a new class of checkpoint blockade antibodies. Specifically, I am using cutting-edge glycoproteomics techniques and a novel synthetic glycopeptide array screening platform to comprehensively elucidate the structural determinants of Siglec binding. Based on promising preliminary data, I expect these experiments to demonstrate that Siglecs bind defined epitopes on cancer cells that can be therapeutically targeted. This work will shed light on a previously understudied mechanism of immune evasion exploited by a significant fraction of tumors, and open the door to a new strategy for immunotherapy applicable to diverse cancers.