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"Stone, Meredith L"
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Disney Princess storybook collection
A collection of 19 stories featuring princesses from Disney films.
BOOK
Hepatocytes direct the formation of a pro-metastatic niche in the liver
The liver is the most common site of metastatic disease
1
. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver
2
,
3
. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.
Pancreatic cancer activates IL-6–STAT3 signalling in hepatocytes to induce the formation of a pro-metastatic niche in the liver.
Journal Article
Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden
Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45⁺ immune cells and the percentage of active CD8⁺ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.
Journal Article
Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice
Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.
The liver is the most common site of metastasis for pancreatic ductal adenocarcinoma (PDAC). Here, the authors demonstrate that β-glucan, a microbial component associated with trained immunity, activates liver-resident macrophages (Kupffer cells) and prevents PDAC metastasis to the liver
Journal Article
IFN-γ–driven skewing towards Th1 over Th17 differentiation underlies CRS and neutropenia in CAR-T therapy
Chimeric antigen receptor T cell (CAR-T) therapy has led to significant improvements in patient survival. However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematological toxicity (ICAHT). We utilized IL-2Ra knockout mice to model toxicities with elevated levels of IL-6, IFN-γ, and TNF-α and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils. Both nontumor-bearing and Em-ALL tumor-bearing mice recapitulated the cooccurrence of CRS and neutropenia. IFN-γ-blockade alleviated CRS and neutropenia without affecting CAR-T efficacy. Mechanistically, a Th1-Th17 imbalance was observed to drive cooccurrence of CRS and neutropenia in an IFN-γ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN-γ-to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia. We have uncovered a biological basis for ICAHT and provide support for the use of IFN-γ blockade to reduce both CRS and neutropenia.
Journal Article
Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins
T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8
+
T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.
Here the authors show how the liver affects the immune response to pancreatic ductal adenocarcinoma and that cancer immunity and survival outcomes after surgery might be bolstered by therapeutic intervention on hepatocyte release of serum amyloid A proteins.
Journal Article
TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy
Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.
Journal Article
REPLY TO HAFFNER ET AL
In the letter by Haffner et al, they report that seminoma cell-intrinsic DNA hypomethylation is associated with endogenous retroviral expression, an IFN response, and lymphocytic infiltration. Their data complement and support our recent therapeutic study in a mouse model of ovarian cancer and support our observations that low doses of the DNA methyltransferase inhibitor azacytidine (AZA), in combination with the histone deacetylase inhibitor, givinostat, activate type 1 IFN signaling in ovarian and lung cancer cells to increase numbers and activation of immune cells in the tumor microenvironment and to increase sensitivity to the immune checkpoint inhibitor anti-PD1. We and others have shown that this AZA-induced immunogenic response is dependent on the reexpression of endogenous retroviruses and an innate immune response. Taken together, these data suggest that a combination of DNA demethylation and immunotherapy may be a therapeutically attractive strategy, for which clinical trials are already in progress.
Journal Article
Creating a Culturally Sensitive Onboarding Process: Experiences Through the Lens of African American Nursing Students
Background: Racial minorities in the United States comprises 40% of the population. 19.5% of nursing workforce is diverse yet only 5.5% identify as African American. Work is needed to diversify nursing school enrollment to increase the diversity in the nursing workforce.Purpose: Purpose of this project is to explore the phenomenon of interest by participation in one of two focus groups.Methods: A qualitative descriptive design was utilized. A sample of 12 completed a focus group interview, answering seven questions with probes interjected.Results: Three themes were identified of financial challenges, language barrier, and time. Three subthemes were also categorized as cultural influences, technology, and spirituality.Discussion: Finances and lack of resources or hesitancy to access resources is prevalent. Nontraditional student with unique family demands creates additional stressor. Slight variations from British English to American English causes difficulty with meeting admission requirements, writing assignments, and standardized testing. Spoken language and having an accent produces a fear of judgement and misinterpretation of lack of knowledge. Lack of time for completion of tasks requiring often translational skills. The second concept is the perception of time and laidback nature produces difficulty to be timely which is the cultural norm of the dominant culture.Conclusion: Many barriers exist that impact outcomes and success for African American pre-licensure nursing students. Culture and spirituality influence the student experience. Research is needed to improve retention and success for these students.
Dissertation