Our Science – Wiltrout Website
Robert H. Wiltrout, Ph.D.
Dr. Wiltrout is the holder of six patents in the area of immune response and hematopoietic regulation. He has been an organizer and/or plenary speaker at numerous national and international symposia in the areas of biological therapy of cancer, the regulation of immune responses in the tumor microenvironment, and mouse models of liver cancer. He is the author of more than 200 scientific publications in the areas of innate immunity, inflammation and cancer immunotherapy.
Inflammation and Experimental Immunotherapy for Kidney and Liver Cancers in the Mouse Models
The mechanisms by which the immune system can contribute to promotion or inhibition of cancers in vivo are complex and incompletely understood. Successful induction of cytokine-induced tumor regression depends on a complex interplay between critical elements of the innate immune system (dendritic cells and NK or NKT cells) and classical elements of the adaptive immune response such as CD4+ or CD8+ T cells, and the ability to mitigate the immunosuppressive effects of T regulatory (Tregs), myeloid-derived suppressor cells (MDSC), and their active mediators. In particular, successfully engaged innate mechanisms may trigger inflammatory events in the tumor microenvironment that, in turn, minimize the effects of Tregs and MDSC, resulting in overall instructive signals for the development of beneficial adaptive responses. In this regard, we have focused our efforts on 1) the immune-regulating and cancer therapeutic potential of IL-12 and IL-18, and the role of IFN-gamma in the innate and adaptive immune response; 2) approaches for coordinating the beneficial effects of innate and adaptive responses with a mitigation of Treg and MDSC-mediated inhibitory effects via stimulation of the CD40 receptor on antigen presenting cells in concert with IL-2 or IL-15 treatment; and 3) understanding unique microenvironmental dynamics and influences in the lungs and liver as models for organ-specific immunotherapy.
We have also used Sleeping Beauty-mediated, in vivo genetic modification of hepatocytes with dysregulated AKT, MET, and beta-catenin genes to develop several reproducible, clinically-relevant, subtype-specific models of oncogene-initiated liver cancers and are using them to explore the intersection between oncogenesis and pathways of inflammation. Our current effort is focused on the role of TNF-family members in the development and progression of oncogene-initiated liver cancers. In particular, we are investigating the role of activation through the lymphotoxin beta receptor (LTbetaR) on the biology of both hepatocellular adenomas and carcinomas, as well as the development of cholangiocarcinomas. Our current studies are focused on the downstream molecular signaling pathways and immune perturbations associated with the LTbetaR-dependent events and possible ways to modify liver tumor outcome through targeting of the LTbetaR.
The overall goal of our studies is to provide new insights into complex immune interactions in vivo and develop preclinical approaches for the use of immunotherapy, alone and in combination with other molecularly targeted strategies, for translation to clinical trials in cancer patients.
Collaborators on this project include Giorgio Trinchieri, John R. Ortaldo, Thomas J. Sayers, Snorri Thorgeirsson, Curt Harris, Perwez Hussain, David A. Wink, Xin Wang, and Howard A. Young, NIH; William J. Murphy, University of California at Davis; Bruce Blazar, University of Minnesota; Carl Ware, University of California, San Diego.
This page was last updated on 5/21/2014.