Amy Jo Casbon - Academia.edu (original) (raw)

Papers by Amy Jo Casbon

Frontiers in immunology, Jun 24, 2024

Cancer Immunology, Immunotherapy

Type I interferon-mediated activation of immune cells can facilitate the generation of productive... more Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can p...

Frontiers in Immunology, Oct 23, 2023

Flavocytochrome b558, the catalytic core of the phagocytic NADPH oxidase, mediates the transfer o... more Flavocytochrome b558, the catalytic core of the phagocytic NADPH oxidase, mediates the transfer of electrons from NADPH to molecular oxygen to generate superoxide for host defense. Flavocytochrome b is a membrane heterodimer consisting of a large subunit gp91phox (NOX2) and a smaller subunit, p22phox. Localization of flavocytochrome b to the phagosome is essential for microbial killing, yet the subcellular distribution of flavocytochrome b in macrophages and how it is incorporated into macrophage phagosomes is not well characterized. In neutrophils, flavocytochrome b localizes primarily to specific granules that are rapidly mobilized to the phagosome upon stimulation. In contrast to neutrophils, macrophages do not contain specific granules, and trafficking of membrane proteins to the phagosome is more dynamic, involving fission and fusion events with endosomal compartments. We hypothesized that in macrophages, flavocytochrome b localizes to both plasma membrane and endosomal compart...

Advances in experimental medicine and biology, 2002

Keratoconjunctivitis sicca, or dry eye, is characterized by decreased lacrimal fluid secretion. S... more Keratoconjunctivitis sicca, or dry eye, is characterized by decreased lacrimal fluid secretion. Since this disease is more prevalent in females than males, it has generally been assumed that the sex hormones are involved in its etiology. The sex steroids and the sexually dimorphic peptide hormone prolactin have been under investigation. There have been several reports that reveal a negative correlation between high levels of prolactin and lacrimal gland function. Studies with hypophysectomized rats1 and with human subjects suggest that excessive levels of circulating prolactin (PRL) impair lacrimal secretion.2 Prolactin levels are higher in females than males and rise during pregnancy, in accord with decreased lacrimal function (Schechter et al., unpublished data). Prolactin also seems to be closely linked to autoimmune diseases such as Sjogren’s Syndrome. Big prolactin, 60kD, is found to be overexpressed in salivary glandular epithelial cells of Sjogren’s syndrome patients,3 and hy...

Investigative Ophthalmology & Visual Science, 2014

Cancer Research, 2018

A myriad of combination immunotherapies is being developed as cancer treatments with the goal of ... more A myriad of combination immunotherapies is being developed as cancer treatments with the goal of enhancing antitumor immunity. We found that depending on the disease setting, combined immune checkpoint blockade may not always lead to synergistic antitumor effects. While combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise antitumor immunity in the low tumor burden state in preclinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced apoptosis of tumor-specific T cells. These changes further alter the overall T-cell receptor repertoire. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. Deficiency of IFN-γ receptor on immune cells rescues this phenotype and restores antitumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their ...

Immunity, 2019

Highlights d Combination checkpoint blockade leads to impaired efficacy with low tumor burden d T... more Highlights d Combination checkpoint blockade leads to impaired efficacy with low tumor burden d This impairment results from IFN-g-mediated deletion of tumor-reactive T cells d AICD is an immune-intrinsic mechanism of therapeutic resistance to checkpoint blockade

Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2018

Bone metastasis involves dynamic interplay between tumor cells and the local stromal environment.... more Bone metastasis involves dynamic interplay between tumor cells and the local stromal environment. In bones, local hypoxia and activation of the hypoxia-inducible factor (HIF)-1α in osteoblasts are essential to maintain skeletal homeostasis. However, the role of osteoblast-specific HIF signaling in cancer metastasis is unknown. Here, we show that osteoprogenitor cells (OPCs) are located in hypoxic niches in the bone marrow and that activation of HIF signaling in these cells increases bone mass and favors breast cancer metastasis to bone locally. Remarkably, HIF signaling in osteoblast-lineage cells also promotes breast cancer growth and dissemination remotely, in the lungs and in other tissues distant from bones. Mechanistically, we found that activation of HIF signaling in OPCs increases blood levels of the chemokine C-X-C motif ligand 12 (CXCL12), which leads to a systemic increase of breast cancer cell proliferation and dissemination through direct activation of the CXCR4 receptor...

Revue du Rhumatisme, 2016

par les patients répondeurs EULAR, illustrant le lien entre bon contrôle de la PR et amélioration... more par les patients répondeurs EULAR, illustrant le lien entre bon contrôle de la PR et amélioration du profil CV. Conflit d'intérêt.-aucun O.35 Traitement de la polyarthrite rhumatoïde du sujet âgé (COHORTE CORPUS)

Developmental Cell, 2015

Highlights d Adaptive immune responses regulate postnatal organogenesis of an epithelial tissue d... more Highlights d Adaptive immune responses regulate postnatal organogenesis of an epithelial tissue d Epithelial-associated antigen-presenting cells negatively regulate MG organogenesis d Antigen-mediated interactions with CD4+ T helper 1 cells regulate MG organogenesis d IFNg, produced by T helper 1 cells, affects luminal epithelial differentiation

OncoImmunology, 2015

The accuracy of the Content should not be relied upon and should be independently verified with p... more The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden.

Molecular Cancer Research, 2013

In 1863, Virchow hypothesized that the cancer originated at sites of chronic tissue injury and th... more In 1863, Virchow hypothesized that the cancer originated at sites of chronic tissue injury and that the ensuing inflammation they cause enhances cell proliferation. While it is now clear that proliferation of tumor cells alone does not cause cancer, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma certainly potentiates and/or promotes neoplastic risk and leads to metastasis. In fact, sometimes the trigger for neoplastic progression may come from signals within the stromal microenvironment. The stromal microenvironment consists of fibroblasts, macrophages, neutrophils, vascular components, nerves and inflammatory cells of the innate and acquired immune response, as well as the extracellular matrix that they elaborate along with the molecules that are concentrated and immobilized on it. All of these components communicate with each other and with the neoplastic cells to contribute to the aberrant tumor organ. Factors elaborate...

Cancer Research, 2015

The major cause of cancer-associated mortality is metastasis, but our understanding of this proce... more The major cause of cancer-associated mortality is metastasis, but our understanding of this process is far from complete. Tumor cells invade the surrounding tissue of the primary tumor, intravasate into blood and lymphatic vessels, survive and translocate to distant tissues, extravasate, adapt to the new microenvironment and eventually seed, proliferate and colonize to form metastases. Nearly 125 years ago, Paget enunciated the seed and soil hypothesis of cancer. More recently, emerging data suggested that the cellular and extracellular matrix (ECM) microenvironments—both in the primary tumor and in metastatic sites—are crucial at multiple stages of metastasis. Significantly, targeting the tumor microenvironment in metastasis might hold promise for therapy as stromal cells are not mutated and the effects may be widespread as the ECM interacts with multiple tumor cells. The ECM, which is a rich reservoir of pro- and anti-angiogenic cues that regulate neovascularization of the tumor, a crucial process in tumor cell dissemination. The developing metastatic lesions result from a complex crosstalk between disseminating tumor cells and the different players in the microenvironment of the metastatic lesion. The specific recruitment of distinct populations of leukocytes and stromal cells with overlapping functions in metastasis, may open new avenues to the development of metastasis-targeted therapies. Finally, the function of the tumor microenvironment in modulating sensitivity to chemotherapy is of clinical importance. But the aspects of the microenvironment contribute to loss of drug efficacy are still poorly understood in the metastatic setting. The microenvironment is an important source of anticancer drug resistance and also a therapeutic target, as drugs might not need to be completely penetrant to be effective because altering some immune cells, ECM components or the vasculature may have profound effects as seen with regulation of microRNAs. The microenvironment faced by cells at metastatic sites also determines whether these cells die, proliferate or become dormant. How does the microenvironment evolve from the pre-metastatic stage to established metastases? Determining whether the metastatic niche arises from changes in the ECM, decreased immune surveillance or changes in specific pro-inflammatory molecules poses a challenge for the future. We need a more complete understanding of the role of the metastatic microenvironment to uncover how these processes promote metastasis. Chou, J., J.H. Lin, A. Brenot, J.-w. Kim, S. Provot & Z. Werb (2013). GATA3 suppresses metastasis and modulates the tumor microenvironment by regulating miR-29 expression. Nat. Cell Biol. 15: 201-213. PMCID: PMC3660859. Egeblad, M., A. J. Ewald, H. A. Askautrud, B. E. Welm, M. Truitt, E. Bainbridge, G. Peeters, M. Krummell & Z. Werb (2008). Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis. Model. Mech. 1:155-167. PMCID: PMC2562195. Kessenbrock, K., G.J.P. Dijkgraaf, D. A. Lawson, L. E. Littlepage, P. Shahi, U. Pieper & Z. Werb (2013). A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway. Cell Stem Cell. 13:300-313. PMCID: PMC3769456. Lu, P., V. M. Weaver & Z. Werb (2012). Extracellular matrix: a dynamic niche component during cancer progression. J. Cell Biol. 196:396-406. PMCID: PMC3283993. Nakasone, E., H. A.Askautrud, T. Kees, V. Plaks, A. J. Ewald, M. G. Rasch, Y. X. Tan, J. Qin, M. Fein, J. Park, P. Sinha, M. J. Bissell, E. Frengen, Z. Werb & M. Egeblad (2012). Imaging tumor-stroma interactions during chemotherapy reveals microenvironmental contributions to chemoresistance. Cancer Cell. 21:488-503. PMCID: PMC3332002. Citation Format: Amy-Jo Casbon, Vicki Plaks, Zena Werb. Building the metastatic microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA09. doi:10.1158/1538-7445.CHTME14-IA09

Proceedings of the National Academy of Sciences, 2015

SignificanceWe show that tumor reprogramming of hematopoiesis in bone marrow occurs at the onset ... more SignificanceWe show that tumor reprogramming of hematopoiesis in bone marrow occurs at the onset of malignant conversion and results in systemic expansion of circulating activated neutrophils that preferentially accumulate in lungs. Our data are, to our knowledge, the first to show that activation and not inhibition of myeloid differentiation is responsible for expansion and activity of T cell-suppressive myeloid cells; a tumor-derived factor targets the immature hematopoietic compartment to drive myeloid expansion; granulocyte-colony stimulating factor (G-CSF) is the only hematopoietic growth factor to increase in serum during early tumor development; prolonged G-CSF induces production of Rb1lowneutrophils and not short-term mobilization; and G-CSF acts in a cell intrinsic manner to expand multipotent progenitors to increase production of tumor-derived Ly6G+neutrophils.

Proceedings of the National Academy of Sciences of the United States of America, Jan 25, 2014

Tumor-infiltrating inflammatory cells comprise a major part of the stromal microenvironment and s... more Tumor-infiltrating inflammatory cells comprise a major part of the stromal microenvironment and support cancer progression by multiple mechanisms. High numbers of tumor myeloid cells correlate with poor prognosis in breast cancer and are coupled with the angiogenic switch and malignant progression. However, the specific roles and regulation of heterogeneous tumor myeloid populations are incompletely understood. CSF-1 is a major myeloid cell mitogen, and signaling through its receptor CSF-1R is also linked to poor outcomes. To characterize myeloid cell function in tumors, we combined confocal intravital microscopy with depletion of CSF-1R-dependent cells using a neutralizing CSF-1R antibody in the mouse mammary tumor virus long-terminal region-driven polyoma middle T antigen breast cancer model. The depleted cells shared markers of tumor-associated macrophages and dendritic cells (M-DCs), matching the phenotype of tumor dendritic cells that take up antigens and interact with T cells....