A central challenge in the treatment of cancer patients is to find a primary, pragmatic approach to tackle the interrelated problems of genetic heterogeneity and acquisition of resistance to available therapies by cancers. Among the human malignancies, primary liver tumors account for 9% of all cancer deaths worldwide and 12% in developing countries. HCC accounts for up to 85% of liver cancers and is one of the leading lethal malignancies worldwide. Chronic liver damage caused by viral infection (HBV and HCV), alcohol, non-alcoholic fatty liver disease (NAFLD) or a combination of these factors increases the risk for HCC. Notably, NAFLD, a hepatic manifestation of metabolic syndrome, affects nearly 25% of the US population, and its incidence is rapidly increasing since obesity and metabolic syndrome are growing epidemics worldwide. Although the risk factors are well defined, HCC is still a disease with poor outcome and limited therapeutic options. In fact, major obstacles for effective treatment of this cancer is that HCC is frequently resistant to chemotherapy and radiotherapy, and there is a high frequency of tumor recurrence after curative surgical resection. This prompts the need for greater understanding of the mechanisms underlying liver cancer cell plasticity and adaptation, as well as developing novel therapeutic approaches to achieve more effective and selective cure of this disease. Hsf1 is the master activator of the classical heat shock response and is the guardian of the proteome, and has been implicated in the pathogenesis of cancer. We have discovered that genetic inactivation of Hsf1 in mouse cancer models leads to remarkable inhibition of HCC development. On the basis of published and preliminary studies we propose a novel pathogenic mechanism whereby Hsf1 activation promotes HCC development by stimulating anabolic metabolic pathways (lipid synthesis and glucose production) and perpetuating chronic hepatic metabolic disease. The overall goal of this Revision is to establish that Hsf1 acts as the central node of a regulatory network that enables malignant cells to escape immune surveillance, interfering with anti-tumor CD8+ T cell-mediated immunity through reprogramming metabolic pathways within T cells (intrinsic) or in the tumor microenvironment. Reversing these intrinsic and non-cell autonomous metabolic effects by inactivation of Hsf1 will facilitate the generation and maintenance of long-lasting CD8+ T cells with superior anti-tumor capacity. The experimental strategy entails the following two major approaches: 1. To investigate the effects of Hsf1 deletion on metabolic reprogramming and anti-tumor CD8+ T cell response, and 2. To investigate the impact of Hsf1 deletion on improved CD8+ T cell-based immunotherapy for HCC. In summary, the long-term translational goal of the project is to provide proof-of-concept for targeting HSF1-mediated metabolic programs for immunotherapeutic application of liver cancer. However, we expect that the results will have profound implications to improve immunotherapeutic interventions to tackle other solid cancer types.
The results of our studies should have major implications for an understanding of the prognostic and therapeutic value of metabolic alterations caused by Hsf1 inactivation in improving anti-tumor adaptive immunity. This research will also provide the rationale to develop novel T cell-based immunotherapy strategies to prevent, and perhaps treat, diverse malignancies, including liver cancers, that arise on the background of chronic injury due to genomic mutations and alterations in metabolic and protein homeostasis pathways.
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