Abstract B141: Anti-Lymphocyte Antigen 6D (LY6D) monoclonal antibody inhibits pancreatic tumor growth in vivo by downregulating the TGFb-Smad2 signaling

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States and is associated with dismal prognosis. Recent studies revealed that LY6D expression is elevated in PDAC and correlates with poor patient survival. However, the functional role of LY6D in PDAC progression remains undefined. Here, we demonstrate that LY6D is required for pancreatic tumor growth in vivo. We found that mechanistically, LY6D regulates a Smad2-driven transcriptional program that modulates the expression of multiple cytokines, including IL6, as well as clinically relevant biomarkers such as MUC1 and CEACAM5. In addition, LY6D enhances the expression of immune-related genes, including MHC class I and II molecules. Functionally, elevated LY6D expression diminishes the sensitivity of PDAC cells to gemcitabine, highlighting its role in therapy resistance. To therapeutically target LY6D, we developed three distinct novel anti-LY6D monoclonal antibodies, which directly inhibited PDAC cell growth. Additionally, the monoclonal antibodies mediated potent antibody-dependent cellular cytotoxicity (ADCC). We found that anti-Ly6D antibody treatment synergizes with Gemcitabine treatment. Collectively, these findings identify LY6D as a critical regulator of PDAC progression and establish LY6D-targeted antibody therapy as a promising therapeutic avenue for patients with LY6D-expressing tumors including pancreatic and breast cancers.