Engineered fusion cytokine Siglec G - GMCSF modulate the tumor microenvironment and improve tumor immunogenicity 2113

Abstract Description Targeting sialic acid could serve as a strategic approach to slow down tumor invasion and provide potential for prophylactic therapies. Siglec 10 is an inhibitory receptor of the innate immune system, which binds to glycosylated CD24 on the tumor surface, and promotes immune escape. Siglec G, its murine ortholog, is designed to fuse with GM-CSF, an adjuvant cytokine which stimulates the development of dendritic cells. This novel fusion cytokine (SG) is aimed at targeting tumor-expressed CD24 cells, enhancing the efficacy of immune infiltration and modulation in the tumor microenvironment. We have designed multiple versions of fusokines to maintain the steric conformation of each component. Transiently transfected into 293T cells, these clones demonstrate the ability to exhibit biological activity of either Siglec G or GM-CSF. We then establish stable cancer cell clones expressing SGs to evaluate their immune adjuvant effects in vivo. After the successful subcutaneous implantation, one SG construct appears to trigger M1 initiation, DC infiltration, and T cell activation. The initially non-responsive KPC tumor is eliminated and shows immunogenicity upon rechallenge. Next, we treat KPC tumor-bearing mice with recombinant protein. rSG significantly reduces tumor growth compared to the control groups. Our goal is to translate this finding into a cancer vaccine approach and in combination with immune therapy. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)