Browsing by Author "Franco, Jorge"
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Item Disease Exacerbation in Multiple Sclerosis Patients is Characterized by Loss of Terminally Differentiated CD8+ T Regulatory Cells(2014-02-04) Cunnusamy, Khrishen; Baughman, Ethan J.; Franco, Jorge; Ortega, Sterling B.; Greenberg, Benjamin M.; Frohman, Elliot M.; Karandikar, Nitin J.Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that afflicts more than 400,000 people in the US. Although the etiology of the disease is unknown, pathogenic T cells are thought to underlie MS immune pathology. In contrast to the current paradigm, we recently showed that MS patients harbor CNS-specific CD8+ T regulatory cells (CD8 Tregs) that are deficient during disease relapse. In the current study, we demonstrate that the neuroantigen-specific CD8 Tregs were cytolytic and eliminated pathogenic CD4+ T cells. Sorting of CD8+ T cells using an array of surface cellular markers revealed that the CD8 Tregs were terminally differentiated (CD27-, CD45RO-). The CD8 Treg-mediated suppression was perforin, granzyme B, and interferon-γ-dependent. Interestingly, we found that MS patients with acute disease exacerbation displayed a significant loss (averaging 25%) in the terminally differentiated CD8+ T cells, with a concurrent loss in perforin and granzyme B expression. In order to restore the regulatory potential of impaired CD8 Tregs during exacerbation, we pre-treated exacerbation-derived bulk CD8+ T cells with the cytokine IL-12 and significantly increased the suppressive capability of the cells by ~48% through upregulation of granzyme B and perforin. Our studies uncover the immune suppressive mechanism of neuroantigen-specific CD8 Tregs, and may contribute to the design of clinically relevant immune therapies for MS patients.Item Targeting Cyclin Dependent Kinases 4/6 Activity in Pancreatic Ductal Adenocarcinoma(2016-06-06) Franco, Jorge; Brekken, Rolf A.; Burma, Sandeep; Pearson, Gray W.; Knudsen, Erik S.Pancreatic ductal Adenocarcinoma (PDA) is an aggressive and lethal disease that lacks an adequate treatment. Given that patients with PDA only marginally benefit from the current therapies, there is an urgent need to develop more effective approaches that specifically target PDA. Because a significant portion of PDA tumors lose p16 expression and often over-express Cyclin D1, we hypothesized that CDK4/6 activity is deregulated leading to uncontrolled proliferation. Thus, PDA would represent a good candidate for treatment with recently developed CDK4/6 inhibitors. Our study first investigated the sensitivity of PDA cells to CDK4/6 inhibition and found that PDA cells exhibit variable responses to CDK4/6 inhibition, incling models that display significant resistance. Interestingly, these models showed a novel mechanism of resistance to CDK4/6 inhibition. Prior to this study, RB loss was the only mechanism known to circumvent CDK4/6 inhibition. However, herein, we uncovered that CDK4/6 inhibition can lead to aberrant Cyclin E expression, which can compensate for CDK4/6 activity loss and maintain RB in a hyper-phosphorylated state. Subsequent findings demonstrated that this resistance could be blocked by combination therapy with MTOR inhibitors, which prevented aberrant Cyclin E expression and reinforced RB activation. Our second study found that prolonged CDK4/6 inhibition led to an altered metabolic state with an increased in oxidative respiration and glycolysis accompanied by mitochondria accumulation and increase cellular complexity. This heightened metabolic state was mediated by MTOR signaling, which activity was stimulated by amino acid accumulation and an increase in lysosome production in CDK4/6 treated PDA cells. Lastly, we unveiled new combination therapies that targeted the altered metabolism state of CDK4/6 inhibitor treated cells by impinging on antioxidants such as Hemoxygenase 1 (HO-1) and catalase (CAT), whose expression was enhanced post treatment, or by targeting BCL-2/BCL-XL using ABT-737. Taken together our data demonstrate that targeting PDA with CDK4/6 inhibitors can represent an efficacious route for treatment. Activation of MTOR and perhaps other signaling pathways likely contribute to intrinsic and acquired resistance to CDK4/6. These combined data would support the combined use of CDK4/6 with MTOR inhibitors and other agents for the treatment of pancreatic cancer.