Browsing by Author "Cannon, Anthony"

Now showing 1 - 4 of 4
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    HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer
    (Taylor & Francis, 2024-06-05) Ramos Solis, Nicole; Cannon, Anthony; Dilday, Tinslee; Abt, Melissa; Oblak, Adrian L.; Soloff, Adam C.; Kaplan, Mark H.; Yeh, Elizabeth S.; Pharmacology and Toxicology, School of Medicine
    Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.
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    Interleukin-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration in allergic airway inflammation
    (Elsevier, 2023) Pajulas, Abigail; Fu, Yongyao; Cheung, Cherry C. L.; Chu, Michelle; Cannon, Anthony; Alakhras, Nada; Zhang, Jilu; Ulrich, Benjamin J.; Nelson, Andrew S.; Zhou, Baohua; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    Allergic asthma is a chronic lung disease characterized by airway hyperresponsiveness and cellular infiltration that is exacerbated by immunoglobulin E-dependent mast cell (MC) activation. Interleukin-9 (IL-9) promotes MC expansion during allergic inflammation but precisely how IL-9 expands tissue MCs and promotes MC function is unclear. In this report, using multiple models of allergic airway inflammation, we show that both mature MCs (mMCs) and MC progenitors (MCp) express IL-9R and respond to IL-9 during allergic inflammation. IL-9 acts on MCp in the bone marrow and lungs to enhance proliferative capacity. Furthermore, IL-9 in the lung stimulates the mobilization of CCR2+ mMC from the bone marrow and recruitment to the allergic lung. Mixed bone marrow chimeras demonstrate that these are intrinsic effects in the MCp and mMC populations. IL-9-producing T cells are both necessary and sufficient to increase MC numbers in the lung in the context of allergic inflammation. Importantly, T cell IL-9-mediated MC expansion is required for the development of antigen-induced and MC-dependent airway hyperreactivity. Collectively, these data demonstrate that T cell IL-9 induces lung MC expansion and migration by direct effects on the proliferation of MCp and the migration of mMC to mediate airway hyperreactivity.
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    Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9
    (Springer Nature, 2022-07-01) Fu, Yongyao; Pajulas, Abigail; Wang, Jocelyn; Zhou, Baohua; Cannon, Anthony; Cheung, Cherry Cheuk Lam; Zhang, Jilu; Zhou, Huaxin; Fisher, Amanda Jo; Omstead, David T.; Khan, Sabrina; Han, Lei; Renauld, Jean-Christophe; Paczesny, Sophie; Gao, Hongyu; Liu, Yunlong; Yang, Lei; Tighe, Robert M.; Licona-Limón, Paula; Flavell, Richard A.; Takatsuka, Shogo; Kitamura, Daisuke; Sun, Jie; Bilgicer, Basar; Sears, Catherine R.; Yang, Kai; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c- interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r-/- mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.
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    The Dichotomy of Interleukin-9 Function in the Tumor Microenvironment
    (Mary Ann Liebert, 2023) Cannon, Anthony; Pajulas, Abigail; Kaplan, Mark H.; Zhang, Jilu; Microbiology and Immunology, School of Medicine
    Interleukin 9 (IL-9) is a cytokine with potent proinflammatory properties that plays a central role in pathologies such as allergic asthma, immunity to parasitic infection, and autoimmunity. More recently, IL-9 has garnered considerable attention in tumor immunity. Historically, IL-9 has been associated with a protumor function in hematological malignancies and an antitumor function in solid malignancies. However, recent discoveries of the dynamic role of IL-9 in cancer progression suggest that IL-9 can act as both a pro- or antitumor factor in various hematological and solid malignancies. This review summarizes IL-9-dependent control of tumor growth, regulation, and therapeutic applicability of IL-9 blockade and IL-9-producing cells in cancer.