Browsing by Author "Lenz, Laurel"

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    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 Medicine
    STAT3 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.
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    Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma
    (American Association for Cancer Research, 2022) Piper, Miles; Van Court, Benjamin; Mueller, Adam; Watanabe, Shuichi; Bickett, Thomas; Bhatia, Shilpa; Darragh, Laurel B.; Mayeda, Max; Nguyen, Diemmy; Gadwa, Jacob; Knitz, Michael; Corbo, Sophia; Morgan, Rustain; Lee, Jung-Jae; Dent, Alexander; Goodman, Karyn; Messersmith, Wells; Schulick, Rich; Del Chiaro, Marco; Zhu, Yuwen; Kedl, Ross M.; Lenz, Laurel; Karam, Sana D.; Microbiology and Immunology, School of Medicine
    Purpose: Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden. Experimental design: PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations. Results: We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets. Conclusions: Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.