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Item Dichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC(Elsevier, 2021) Bickett, Thomas E.; Knitz, Michael W.; Piper, Miles; Oweida, Ayman J.; Gadwa, Jacob; Darragh, Laurel B.; Nguyen, Diemmy; Bhatia, Shilpa; Bhuvane, Shiv; Phan, Andy V.; Van Court, Benjamin; Corbo, Sophia; Pham, Tiffany; Dent, Alexander L.; Lenz, Laurel; Karam, Sana D.; Microbiology and Immunology, School of MedicineSTAT3 signaling has been shown to regulate cellular function and cytokine production in the tumor microenvironment (TME). Within the head and neck squamous cell carcinoma (HNSCC) TME, we previously showed that therapeutic targeting of STAT3 in combination with radiation resulted in improved tumor growth delay. However, given the independent regulatory effects STAT3 has on anti-tumor immunity, we aimed to decipher the effects of individually targeting STAT3 in the cancer cell, regulatory T cells (Tregs), and natural killer (NK) cell compartments in driving tumor growth and resistance to therapy in HNSCCs. We utilized a CRISPR knockout system for genetic deletion of STAT3 within the cancer cell as well as two genetic knockout mouse models, FoxP3-Cre/STAT3 fl and NKp46-Cre/STAT3 fl, for Tregs and NK cell targeting, respectively. Our data revealed differences in development of resistance to treatment with STAT3 CRISPR knockout in the cancer cell, driven by differential recruitment of immune cells. Knockout of STAT3 in Tregs overcomes this resistance and results in Treg reprogramming and recruitment and activation of antigen-presenting cells. In contrast, knockout of STAT3 in the NK cell compartment results in NK cell inactivation and acceleration of tumor growth. These data underscore the complex interplay between the cancer cell and the immune TME and carry significant implications for drug targeting and design of combination approaches in HNSCCs.Item Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion Through Paracrine Factors(Sage, 2017-02) Xie, Jie; Jones, Thomas J.; Feng, Dongni; Cook, Todd G.; Jester, Andrea A.; Yi, Ru; Jawed, Yameena T.; Babbey, Clifford; March, Keith L.; Murphy, Michael P.; Department of Anesthesia, School of MedicineAbdominal aortic aneurysm (AAA) is a potentially lethal disease associated with immune activation-induced aortic degradation. We hypothesized that xenotransplantation of human adipose-derived stem cells (hADSCs) would reduce aortic inflammation and attenuate expansion in a murine AAA model. Modulatory effects of ADSCs on immune cell subtypes associated with AAA progression were investigated using human peripheral blood mononuclear cells (hPBMNCs) cocultured with ADSCs. Murine AAA was induced through elastase application to the abdominal aorta in C57BL/6 mice. ADSCs were administered intravenously, and aortic changes were determined by ultrasonography and videomicrometry. Circulating monocytes, aortic neutrophils, CD28− T cells, FoxP3+ regulatory T cells (Tregs), and CD206+ M2 macrophages were assessed at multiple terminal time points. In vitro, ADSCs induced M2 macrophage and Treg phenotypes while inhibiting neutrophil transmigration and lymphocyte activation without cellular contact. Intravenous ADSC delivery reduced aneurysmal expansion starting from day 4 [from baseline: 54.8% (saline) vs. 16.9% (ADSCs), n = 10 at baseline, n = 4 at day 4, p < 0.001], and the therapeutic effect persists through day 14 (from baseline: 64.1% saline vs. 24.6% ADSCs, n = 4, p < 0.01). ADSC administration increased aortic Tregs by 20-fold (n = 5, p < 0.01), while decreasing CD4+CD28− (-28%), CD8+CD28− T cells (-61%), and Ly6G/C+ neutrophils (-43%, n = 5, p < 0.05). Circulating CD115+CXCR1−LY6C+-activated monocytes decreased in the ADSC-treated group by day 7 (-60%, n = 10, p < 0.05), paralleled by an increase in aortic CD206+ M2 macrophages by 2.4-fold (n = 5, p < 0.05). Intravenously injected ADSCs transiently engrafted in the lung on day 1 without aortic engraftment at any time point. In conclusion, ADSCs exhibit pleiotropic immunomodulatory effects in vitro as well as in vivo during the development of AAA. The temporal evolution of these effects systemically as well as in aortic tissue suggests that ADSCs induce a sequence of anti-inflammatory cellular events mediated by paracrine factors, which leads to amelioration of AAA progression.Item Regulatory T cell therapy: Current and future design perspectives(Elsevier, 2020-10) Rana, Jyoti; Biswas, Moanaro; Pediatrics, School of MedicineRegulatory T cells (Tregs) maintain immune equilibrium by suppressing immune responses through various multistep contact dependent and independent mechanisms. Cellular therapy using polyclonal Tregs in transplantation and autoimmune diseases has shown promise in preclinical models and clinical trials. Although novel approaches have been developed to improve specificity and efficacy of antigen specific Treg based therapies, widespread application is currently restricted. To date, design-based approaches to improve the potency and persistence of engineered chimeric antigen receptor (CAR) Tregs are limited. Here, we describe currently available Treg based therapies, their advantages and limitations for implementation in clinical studies. We also examine various strategies for improving CAR T cell design that can potentially be applied to CAR Tregs, such as identifying co-stimulatory signalling domains that enhance suppressive ability, determining optimal scFv affinity/avidity, and co-expression of accessory molecules. Finally, we discuss the importance of tailoring CAR Treg design to suit the individual disease.