My research is focused on two R01-funded projects: first, my group has developed a pancreatic cancer immunotherapy research program on a neoadjuvant therapy platform and also a number of preclinical models of pancreatic cancer for developing innovative immunotherapy strategies. My group has also applied the knowledge gained from pancreatic cancer immune-based therapies to the development of a colorectal cancer GVAX vaccine. Second, my group is aimed at understanding the mechanistic roles of tumor microenvironment in cancer development and metastasis and identifying new targets for pancreatic cancer therapies by dissecting tumor microenvironment of pancreatic cancer. Specifically, my laboratory found that the induction of antibodies against annexin A2 (AnxA2) in the sera of pancreatic ductal adenocarcinoma (PDA) patients is associated with longer recurrence-free survival following the GVAX vaccine therapy. By knocking out AnxA2 in a transgenic mouse model of PDA that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 is essential for metastases in vivo. More recently, my laboratory found the expression of semaphorin 3D (Sema3D) and plexin D1 (PlxnD1), which mediate the migration of neuronal axons during development and of blood vessels during angiogenesis, is increased in pancreatic cancer. Our study subsequently elucidated a novel mechanism of PDA metastasis formation that is mediated by AnxA2-dependent Sema3D secretion and subsequent autocrine activation of PlxnD1, the receptor of Sema3D. Studies are underway to uncover the exact processes by which Sema3D and PlxnD1 induce invasion of PDA cells from the primary tumor site into the surrounding blood vessels, nerves and lymphatic vessels. My group is also developing therapeutic agents that target AnxA2 and Sema3D for pancreatic cancer treatment.
- Foley K, Rucki AA, Xiao Q, Zhou D, Leubner A, Mo G, Kleponis J, Wu AA, Sharma R, Jiang Q, Anders RA, Iacobuzio-Donahue CA, Hajjar KA, Maitra A, Jaffee EM, Zheng L. Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer. Science Signaling. 2015; 8(388):ra77. PMID 26243191
- Fu J, Kanne D, Leong M, McWhirter S, Glickman LH, Lemmens E, Mechette K, Leong J, Lauer P, Soares KC, Zheng L., Portnoy DA, Woodward JJ, Pardoll DM, Dubensky Jr. TW, Kim Y. Synthetic cyclic dinucleotide STING agonists formulated into cancer vaccines (STINGVAX) can induce regression of established tumor resistant to immune checkpoint blockade. Science Translational Medicine 2015;7(283):283ra52. PMID 25877890
- Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu L, Yao S, Anders AA, Laheru D, Wolfgang CL, Edil BH, Schulick RD, Jaffee EM, Zheng L., PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T cell infiltration into pancreatic tumors. Journal of Immunotherapy 2015;38(1):1-11. PMID 25415283
- Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, Solt S, Dorman A, Wamwea A, Yager A, Laheru D, Wolfgang CL, Wang J, Hruban RH,. Anders RA, Jaffee EM, Zheng L., Immunotherapy Converts Non-immunogenic Pancreatic Tumors into Immunogenic Foci of Immune Regulation. Cancer Immunology Research 2014;2(7):1-16. PMID 24942756
- Zheng L, Xue J, Jaffee EM, Habtezion A., Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 2013;144(6):1230-1240. PMID 2362213
- Rucki A, Zheng L., Pancreatic cancer stroma: understanding biology leads to therapy. World J Gastroenterol 2014;20(9):2237-2246. PMID 24605023