George Miller, MD
Perlmutter Cancer Center at NYU Langone
Co-PI: Shohei Koide, PhD
Research Project: Central Role of TIM4 in Driving Immune Tolerance in Pancreatic Carcinoma
Award: 2018 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2018 – June 30, 2020
Dr. Miller is a hepatobiliary and pancreatic surgical oncologist at the NYU School of Medicine. His lab studies the role of pancreatic inflammation in the development of pancreatic cancer. His lab is also interested in the critical genes that support cancer formation by suppressing the immune system, the body’s natural defense to fight cancer. Dr. Miller leads an ambitious program developing new drugs that will enable immunotherapies (a type of cancer treatment that improves immune system function) to increase their effectiveness in treating pancreatic cancer patients. He is translating exciting new discoveries in pancreatic cancer research to the clinic. Dr. Miller was the recipient of a 2014 Innovative Grant from PanCAN.
Dr. Koide is a professor in the department of biochemistry and molecular pharmacology at NYU School of Medicine. He received his BSc, MSc and PhD degrees from the University of Tokyo and then underwent his postdoctoral training at the Scripps Research Institute, Calif. Research in his group focuses on the design and engineering of protein recognition interfaces and applications of such “synthetic binding proteins” to biomedically important questions. He has been interested in understanding the molecular mechanisms of cellular signaling and regulation, particularly those controlled by protein-protein interaction, protein conformational change and post-translational modification and in developing new drugs for controlling these processes.
There are many immune cells that surround and enter pancreatic tumors. But efforts to harness the immune system to attack the cancer cells via immunotherapy have failed to show effectiveness in many early clinical trials. A deeper analysis of the inflammatory mediators (substances that initiate or regulate inflammation) in pancreatic cancer provides critical insight to this phenomenon. A type of immune cell called CD4+ T cells can behave in two divergent ways. They can either combat cancer growth or, more commonly, promote tumor progression in mice and correlate with reduced survival in human pancreatic cancer.
Dr. Miller and his colleagues have reported that another immune cell type, called macrophages, control the regulation of CD4+ T cells and control whether they’re immunogenic (able to induce an immune response) or immune-suppressive, preventing the immune system from recognizing and attacking the cancer cells.
Whereas other immunotherapeutic efforts have aimed to directly target the T cells, Drs. Miller and Koide hypothesize that changing and reprogramming the activity of macrophages could effectively shift the balance toward immunogenic CD4+ T cells and activate an immune response.
TIM4 is a transmembrane receptor (a key protein that sits partially inside and partially outside the cell) expressed on macrophages. The investigators’ preliminary data suggest that TIM4 signaling controls macrophage behavior and the capacity of T cells to react to cancer cells. They hypothesize that TIM4 activation is a switch that drives macrophage programming.
Further, they predict that neutralizing TIM4 (blocking its expression or activity) will reprogram macrophages’ and T cells’ functions to combat the cancer instead of promoting it.
The researchers believe targeting TIM4 has high translational potential as a treatment strategy either by itself or in combination with other immunotherapies. They plan to construct a new neutralizing antibody against human TIM4 and test its effectiveness in the lab in human 3D models of the pancreas with a tumor. This will provide a new drug for experimental therapeutics in pancreatic cancer.