University of Miami
Genetic deletion of MALL reprograms tumor microenvironment and improves survival response to anti-PD1 in pancreatic-ductal adenocarcinoma
Overview
Aim: Treatment / Therapy
Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths in the US by the year 2030. The unique tumor microenvironment of PDAC prevents it from responding well to currently available treatments. The PDAC tumor microenvironment is rich in stroma and is known to promote the recruitment of immunosuppressive tumor-associated-macrophages and myeloid-derived-suppressive cells. Consequently, anti-tumor immunity is inhibited by the upregulation of immune checkpoint inhibitors, such as PD-L1 expression. Immunotherapies have not been very successful against PDAC. At present, PDAC remains a lethal disease with poor prognosis since we have not yet identified effective therapeutic targets.
Herein, we propose to determine the role of a poorly studied protein, Mal, T-cell Differentiation Protein-Like (MALL) on the biology of PDAC. MALL is a membrane-protein which localizes in glycolipid-enriched-membrane-domains and facilitates in the apical transport of membrane- and secretory-proteins. MALL expression correlates with poor survival of PDAC patients. Therefore, we propose to investigate the role of MALL in PDAC biology. Our studies have two major goals: 1) to understand how MALL expression remodels the PDAC tumor microenvironment and 2) to determine if inhibition of MALL enhances anti-tumor response and improves the efficacy of immune checkpoint blockade therapy in preclinical models. These studies will advance our understanding of the PDAC tumor microenvironment and lead to the development of potential therapeutic strategies targeting MALL.