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IL-26, a Non-Canonical Mediator of DNA Inflammatory Stimulation, Promotes TNBC Engraftment 2 and Progression in Association with Neutrophils 3 4 Timothy N

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IL-26, a Non-Canonical Mediator of DNA Inflammatory Stimulation, Promotes TNBC Engraftment 2 and Progression in Association with Neutrophils 3 4 Timothy N Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/0008-5472.CAN-18-3825 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Title: IL-26, a non-canonical mediator of DNA inflammatory stimulation, promotes TNBC engraftment 2 and progression in association with neutrophils 3 4 Timothy N. Trotter*1, Casey W. Shuptrine*1, Li-Chung Tsao1, Robert D. Marek2, Chaitanya Acharya1, Jun-ping 5 Wei1, Xiao-Yi Yang1, Gangjun Lei1, Tao Wang1, Herbert Kim Lyerly1, Zachary C. Hartman1,2 6 1 Department of Surgery, Duke University, Durham NC 7 2 Department of Pathology/Immunology, Duke University, Durham NC 8 *Authors contributed equally to this manuscript 9 10 Running Title: IL-26 promotes TNBC progression in concert with neutrophils 11 12 Keywords: Breast cancer, triple-negative breast cancer, inflammation, IL-26, genomic screen 13 14 Corresponding Author: 15 Zachary C. Hartman 16 MSRBI Room 414 Box 2606, Durham NC 27710 17 Phone- 919-613-9110 18 [email protected] 19 20 The authors declare no potential conflicts of interest. 21 22 Word count: Text: 5644 Abstract: 217 23 24 References: 50 25 26 Figure count: 7 27 28 File count: 7 29 30 Significance: Findings identify IL-26 as a unique, clinically relevant, inflammatory amplifier that enhances 31 triple-negative breast cancer engraftment and dissemination in association with neutrophils, which has potential 32 as a therapeutic target. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/0008-5472.CAN-18-3825 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 51 Abstract 52 Interleukin-26 (IL-26) is a unique amphipathic member of the IL-10 family of cytokines that participates 53 in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular 54 transduction and intracellular inflammatory signaling. While IL-26 has almost no described role in cancer, our 55 in vivo screen of inflammatory and cytokine pathway genes revealed IL-26 to be one of the most significant 56 inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer 57 (TNBC). Examination of human breast cancers demonstrated elevated IL-26 transcripts in TNBC specimens, 58 specifically in tumor cells as well as in Th17 CD4+ T-cells within clinical TNBC specimens. IL-26 did not have 59 an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth in vivo required 60 neutrophils. IL-26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively 61 important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL-26 62 vaccine to stimulate antibody production and suppress IL-26 enhanced engraftment in vivo, suggesting that 63 targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in 64 TNBC and other autoimmune diseases. Thus, we identified IL-26 as a novel key modulator of TNBC metastasis 65 and a potential therapeutic target in TNBC as well as other diseases reliant upon IL-26-mediated inflammatory 66 stimulation. 67 68 Introduction 69 Triple-Negative Breast Cancers (TNBC) are a heterogeneous group of cancers that lack activating 70 mutations in typical proto-oncogenes, making targeted therapy difficult compared to other breast cancers 71 (BC)(1,2). However, many TNBC tumors display an inflammatory signature composed of cytokines and 72 chemokines that directly stimulate tumor growth at the primary site, protect tumor initiating cells, enhance 73 dissemination and engraftment in new niches, and ultimately promote overt metastasis (3-6). Cytokines and 74 chemokines produced by TNBC cells also recruit tumor-enhancing innate immune cells to the primary site 75 while systemically mobilizing innate immune cells to distant niches. We and others have previously shown that 76 various cytokine networks are essential for tumor progression, both clinically and in animal models, particularly 77 through a combination of TNBC cell derived Interleukin (IL) -6 and IL-8 (3). Furthermore, animal studies have 78 concluded that inflammation from infiltrating innate immune cells plays a key role in enhancing tumor growth 79 and metastasis (4). Once in the tumor microenvironment (TME), these immune cells are activated to produce 80 even greater inflammation which directly supports tumor growth, invasion, and subsequent metastasis (4,6-9). 81 These data are backed by numerous clinical studies of human TNBC that describe them as highly infiltrated 82 with immune cells – including T cells, neutrophils, and monocyte/macrophage lineage cells – especially when 83 compared to other sub-types of BC (10-12). Nevertheless, which cytokine networks are most important for 84 overall regulation of TNBC progression, or if there are any central regulators that have an outsized impact on 85 patient survival, remain unknown. 86 In order to investigate the role of inflammation in TNBC and narrow down the list of candidates 87 involved in TNBC progression, dissemination, and engraftment, we conducted a focused inflammatory screen 88 of TNBC in vivo, similar to our previous in vivo screen of immune modulator genes (13). Specifically, we 89 modeled multiple stages of BC progression by direct injection into the mammary fat pad (MFP) for engraftment 90 and growth and intra-venous (i.v.) injection via lateral tail vein for dissemination, engraftment, and growth at a 91 metastatic site (lung). These screens revealed interleukin-26 (IL-26) as a significant and novel mediator of 92 progression in both primary and disseminated niches and was validated in multiple TNBC cell lines as well as 93 in BC samples. 94 IL-26 is a 19-kDa α-helical cytokine that belongs to the IL-10 cytokine family (IL-10, IL-19, IL-20, IL- 95 22, IL-24, and IL-26) and has no known homolog in mice (14). IL-26 mRNA has most widely been detected in 96 activated lymphoid cells including Th17 and NK cells (15), but reports of expression in a variety of other cell 97 types are emerging, including monocytes, bronchial epithelial cells, fibroblast-like synoviocytes, and smooth 98 muscle cells (14). IL-26 canonically activates the Jak-Stat3 pathway through binding a heterodimeric complex 99 of IL10RB and IL20RA (16,17). This triggers expression of pro-inflammatory cytokines IL-1β, IL-6, GM-CSF, 100 and TNFα in human monocytes and activates type I (β) and type II (γ) interferons (IFN), as well as induces IL-8 2 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/0008-5472.CAN-18-3825 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 101 and IL-10 expression, in human epithelial cells (14). Recent evidence also suggests that the highly cationic 102 amphipathic properties of IL-26 results in novel functions, such as direct bactericidal activity through pore 103 formation and bacterial-membrane disruption (18). In addition, the amphipathic nature of IL-26 allows it to act 104 as a cell penetrating carrier molecule for DNA, particularly Neutrophil Extracellular Traps (NETs), giving 105 extracellular DNA access to intracellular receptors such as STING and TLR9 (14,18,19). Though the lack of a 106 mouse homolog has made mechanistic studies difficult, mounting clinical data suggests IL-26 is involved in a 107 host of human diseases. High serum levels of IL-26 are observed in patients with contact dermatitis, rheumatoid 108 arthritis, Crohn’s disease, chronic hepatitis C infection, and severe pediatric asthma (14,20). Finally, emerging 109 evidence implicates a role of IL-26 in various cancers. IL-26 mRNA is elevated in biopsies of cutaneous T-cell 110 lymphomas, IL-26 directly promotes proliferation and survival of gastric cancer cells, and elevated IL-26 111 expression is a poor prognostic indicator of both recurrence-free survival and overall survival of hepatocellular 112 carcinoma after surgical resection (21-23). 113 The appearance of IL-26 as a significant target in both shRNA screens, along with the apparent ability of 114 human IL-26 to modulate tumor progression in mice with no native homolog, warranted further investigation. 115 Herein, we demonstrate the role of IL-26 in TNBC engraftment and progression in mice and the conserved 116 ability of IL-26 to elicit DNA-mediated inflammation in mouse cells. Further, our study implicates the effect 117 primarily depends upon neutrophils in the TME, potentially serving as an microenvironmental regulator in 118 orchestrating tumor inflammation by enhancing neutrophil NET DNA stimulation of multiple inflammatory 119 factors, which are collectively important for TNBC. Due to this critical role, we also investigated its therapeutic 120 potential through IL-26-specific vaccine-induced antibodies. In sum, our studies reveal a potentially significant 121 role for IL-26 in TNBC and suggest it as an actionable therapeutic target to suppress inflammation and inhibit 122 TNBC progression. 123 124 Materials and Methods 125 Cell Lines and reagents: MDA-MB-231, HEK293TW, SUM159, SUM149, MDA-MB-468 and 32DC3 cells 126 were acquired from ATCC and through the Duke Cell Culture Facility. Mouse E0771 cells were purchased 127 from CH3 Biosystems (940001). MDA-MB-231-LM2 cells were a kind gift from Joan Massague (24). All cells 128 were cultured according to ATCC and vendor specifications and tested to be free of Mycoplasma and other 129 rodent pathogens (RADIL IMPACT III Test).
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