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Robert H. Wiltrout, Ph.D.
Innate and Adaptive Immune Mechanisms in Cytokine-Mediated Regression of Mouse Kidney and Liver Cancers
The mechanisms by which the immune system can mediate tumor regression in vivo are complex and incompletely understood. Successful induction of cytokine-induced tumor regression may depend on a complex interplay between critical elements of the innate immune system (dendritic cells and NK or NK T 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 several approaches:
Specifically, we are studying the immune-regulating and cancer therapeutic potential of IL-12, IL-18, and the role of IFN-gamma in the innate and adaptive immune response; 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; opportunities for simultaneous engagement of anti-angiogenesis and immune-based strategies for cancer treatment; and analyzing unique microenvironmental dynamics and influences in the lungs and liver as a model for organ-specific immunotherapy.
In addition, the liver, lungs and kidneys serve as unique model organs to understand the mechanisms by which parenchymal cells and leukocytes communicate in different microenvironments. These studies have relevance to understanding the regulation and optimization of development of innate immune responses and their relationship to metastasis formation and disease-induced inflammation. IL-12 and IL-18 are potent immunoregulatory cytokines for natural killer (NK), NKT, and T cells, and they induce beneficial antitumor activities in numerous experimental models. Our results have shown that although both IL-12 and IL-18 induced potent IFN-gamma-dependent anti-metastatic effects, they have very distinctive effects on the NKT/NK subsets in different organs. In addition to studying the different immunoregulatory effects of cytokines on NKT and NK cells, we are also studying the interactions between these two subsets and the relative roles each plays in antitumor defenses.
Most recently, we have applied our findings primarily to mouse models of renal cell cancer (RCC) to develop new immunotherapeutic approaches for the treatment of cancer, and translated them to human clinical trials. We have also developed oncogene-driven models of liver cancer and are using them to study inflammation-driven events in the tumor initiation to progression continuum, and as a complement to our transplantable mouse RCC models for the development of new immunotherapeutic approaches to cancer treatment.
Using the Sleeping Beauty-mediated, in vivo genetic modification of hepatocytes with dysregulated AKT, MET, and β-catenin genes, we developed reproducible, clinically-relevant, subtype-specific models of oncogene-initiated hepatic cancers and are using them to determine how selected innate immune cells of the liver microenvironment respond to the dysregulation of specific oncogenic pathways. Gene expression profiling studies have correlated an inflammatory gene signature with a propensity for metastatic potential in HCC patients. These findings suggest that a better understanding of the role of the immune system may inform new strategies for early intervention/prevention and treatment through the use of immunotherapy in combination with selected molecularly targeted agents.
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 John R. Ortaldo, Thomas J. Sayers, Jon M. Wigginton, Snorri Thorgeirsson, Curt Harris, Perwez Hussain, David A. Wink and Howard A. Young, NIH; William J. Murphy, University of California at Davis; Bruce Blazar, University of Minnesota.
This page was last updated on 11/25/2013.