Showing papers by "Lisa M. Coussens published in 2016"
TL;DR: The results suggest that ferumoxytol could be applied 'off label' to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.
Abstract: Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. Here, we show an intrinsic therapeutic effect of ferumoxytol on the growth of early mammary cancers, and lung cancer metastases in liver and lungs. In vitro, adenocarcinoma cells co-incubated with ferumoxytol and macrophages showed increased caspase-3 activity. Macrophages exposed to ferumoxytol displayed increased mRNA associated with pro-inflammatory Th1-type responses. In vivo, ferumoxytol significantly inhibited growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol treatment before intravenous tumour cell challenge prevented development of liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology studies showed that the observed tumour growth inhibition was accompanied by increased presence of pro-inflammatory M1 macrophages in the tumour tissues. Our results suggest that ferumoxytol could be applied 'off label' to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.
1,089 citations
TL;DR: Developing strategies for neutralizing tumor-promoting inflammation, broadening T-cell repertoires (via vaccination), and elucidating the mechanisms by which immune cells organize tumor microenvironments to regulate T- cell activity will pave the way for identifying new targets for combination therapies that overcome resistance to current treatments and promote long-term cancer control.
608 citations
TL;DR: It is reported that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell-dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy.
Abstract: Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell–dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ+ tumor–associated macrophages, resulting in TH2-type macrophage programming via BTK activation in a PI3Kγ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a TH1 phenotype that fostered CD8+ T-cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacologic inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type.
Significance: We report that BTK regulates B-cell and macrophage-mediated T-cell suppression in pancreas adenocarcinomas. Inhibition of BTK with the FDA-approved inhibitor ibrutinib restores T cell–dependent antitumor immune responses to inhibit PDAC growth and improves responsiveness to chemotherapy, presenting a new therapeutic modality for pancreas cancer. Cancer Discov; 6(3); 270–85. ©2015 AACR .
See related commentary by Roghanian et al., [p. 230][1] .
See related article by Pylayeva-Gupta et al., [p. 247][2] .
See related article by Lee et al., [p. 256][3] .
This article is highlighted in the In This Issue feature, [p. 217][4]
[1]: /lookup/volpage/6/230?iss=3
[2]: /lookup/volpage/6/247?iss=3
[3]: /lookup/volpage/6/256?iss=3
[4]: /lookup/volpage/6/217?iss=3
384 citations
01 Jan 2016
TL;DR: Differences between acute and chronic inflammation in the context of cancer, how each state arises, and how each can be manipulated for development of new cancer therapeutics are outlined.
Abstract: Tissues impacted by chronic infiltration of immune cells, for example, chronic inflammation, have a significantly increased risk of neoplasia. Once tumor development begins, immune cells that infiltrate and subsequently reside within neoplastic microenvironments regulate paracrine pathways in the tissue that foster neoplastic cell survival and proliferation, as well as regulating vascular cells, mesenchymal support cells, and other immune cells to similarly support neoplastic progression and tumor development. We now appreciate that immune microenvironments in solid tumors are targets for anticancer therapy, whereby therapeutics aim to neutralize their tumor-promoting activities, which is coincident with bolstering their embedded activities to foster T cell mobilization and cytotoxic functions through enhanced recognition of tumor-specific antigens. The key leukocytes that contribute to acute versus chronic inflammation in cancer, as well as the mechanisms by which they do so are subjects of the ongoing investigations. This article outlines differences between acute and chronic inflammation in the context of cancer, how each state arises, and how each can be manipulated for development of new cancer therapeutics.
192 citations
TL;DR: Clinical and experimental evidence is discussed supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, and are important contributors to malignancy and potential biomarkers and targets for immunotherapy.
Abstract: Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, and are important contributors to malignancy and potential biomarkers and targets for immunotherapy.
Significance: The tumor microenvironment and tumor-associated inflammation are now appreciated not only for their role in cancer progression but also for their response to therapy. The lymphatic vasculature is a less-appreciated component of this microenvironment that coordinates local inflammation and immunity and thereby critically shapes local responses. A mechanistic understanding of the complexities of lymphatic vessel function in the unique context of skin provides a model to understand how regional immune dysfunction drives cutaneous malignancies, and as such lymphatic vessels represent a biomarker of cutaneous immunity that may provide insight into cancer prognosis and effective therapy. Cancer Discov; 6(1); 22–35. ©2015 AACR .
72 citations
TL;DR: In this paper, ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death using gain-and-loss of function approaches, and miR-103 exacerbates DNA damage and inhibits angiogenesis.
Abstract: Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.
60 citations
TL;DR: It is suggested that antitumor immune responses should be assessed when considering therapeutic options for patients with melanoma after major advances in the treatment of melanoma through the use of targeted therapy and immune checkpoint blockade.
Abstract: We have made major advances in the treatment of melanoma through the use of targeted therapy and immune checkpoint blockade; however, clinicians are posed with therapeutic dilemmas regarding timing and sequence of therapy. There is a growing appreciation of the impact of antitumor immune responses to these therapies, and we performed studies to test the hypothesis that clinical patterns and immune infiltrates differ at progression on these treatments. We observed rapid clinical progression kinetics in patients on targeted therapy compared to immune checkpoint blockade. To gain insight into possible immune mechanisms behind these differences, we performed deep immune profiling in tumors of patients on therapy. We demonstrated low CD8+ T-cell infiltrate on targeted therapy and high CD8+ T-cell infiltrate on immune checkpoint blockade at clinical progression. These data have important implications, and suggest that antitumor immune responses should be assessed when considering therapeutic options for patients with melanoma.
56 citations
TL;DR: The current state of the field is discussed with a focus on the paradoxical outcomes of the senescence-induced inflammatory responses in the context of cancer and factors secreted by senescent cells have been identified in multiple contexts to modulate various aspects of the immune response.
44 citations
TL;DR: This work aims to provide a forward-looking, scalable, and scalable approach to provide real-time information about the Administrator’s decision-making in the management of central giant cell granuloma.
Abstract: * This author contributed to the development and review of this manuscript but is unable to endorse the request for NIH funding .
It is a tremendously exciting time for the cancer community. Thanks to research, we are making significant progress against the many diseases we
36 citations
Casey R. Ager1, Matthew J. Reilley1, Courtney Nicholas1, Todd Bartkowiak1 +1537 more•Institutions (169)
TL;DR: The full contents of the supplement are available online at http://jitc.biomedcentral.com/articles/supplements/volume-4-supplement-1.
Abstract: ### O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells
#### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1,
29 citations
TL;DR: Evidence is provided that deficiency in Trim32 contributes to a T helper type 2 biased response and predisposes to features of AD in mice, and the lower levels of TRIM32 in AD skin compared with healthy control and psoriatic skin suggest a defective TRim32 pathway in AD pathogenesis.
Journal Article•
TL;DR: It is shown that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo and that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors.
TL;DR: CRS-207 has been well tolerated and in combination with chemo showed encouraging anti-tumor activity with 59% response rate and median PFS of 8.5 months; these results appear considerably better than those expected withChemo alone and will be evaluated in a Phase 3 trial.
TL;DR: An approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors through pretreatment prior to an imaging study is shown.
Abstract: Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies.
TL;DR: The randomized, multicenter, double-blind, phase 2/3 RESOLVE trial compares ibr vs. placebo, in combination with Nab-P/GCB, in approximately 320 patients with previously untreated metastatic pancreati...
Abstract: TPS2601Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and short survival. Nab-paclitaxel/gemcitabine (Nab-P/GCB) is a preferred front-line treatment regimen. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (ibr) demonstrates antitumor activity in preclinical PDAC models, due in part to modulation of the tumor microenvironment. Ibr treatment inhibits mast-cell degranulation and decreases tumor-associated inflammation and desmoplasia; simultaneously, ibrutinib enhances the presence and activity of cytotoxic T cells in tumors (Affara et al, Cancer Cell, 2014; Masso-Valles et al, Cancer Res, 2015; Gunderson et al, Cancer Discov, 2015). This study will evaluate the efficacy of ibr in combination with Nab-P/GCB. Methods: The randomized, multicenter, double-blind, phase 2/3 RESOLVE trial (NCT02436668; PCYC-1137-CA) compares ibr vs. placebo, in combination with Nab-P/GCB, in approximately 320 patients with previously untreated metastatic pancreati...
TL;DR: This randomized, multicenter, double-blind RESOLVE trial will compare ibr vs. placebo in combination with Nab-P/GCB in approximately 320 patients with untreated metastatic PDAC.
Abstract: TPS483 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and short survival. Nab-paclitaxel/gemcitabine (Nab-P/GCB) is a preferred regimen for front-line treatment. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (ibr) shows antitumor activity in preclinical PDAC models, in part, due to modulation of the tumor microenvironment. Ibr treatment inhibits mast-cell degranulation and decreases tumor-associated inflammation and desmoplasia with simultaneous enhanced presence and activity of cytotoxic T cells in tumors (Affara et al, Cancer Cell, 2014; Masso-Valles et al, Cancer Res, 2015). This randomized trial will evaluate the efficacy of ibr in combination with Nab-P/GCB. Methods: The randomized, multicenter, double-blind RESOLVE trial (NCT02436668; PCYC-1137-CA) will compare ibr vs. placebo in combination with Nab-P/GCB in approximately 320 patients with untreated metastatic PDAC. Key eligibility criteria include histologically confirmed metasta...
Patent•
18 Nov 2016TL;DR: In this article, the authors describe methods that enable the sequential evaluation of at least seven biomarkers in one formalin-fixed paraffin-embedded (FFPE) tissue section.
Abstract: Immunohistochemical (IHC) techniques that enable the sequential evaluation of at least seven biomarkers in one formalin-fixed paraffin-embedded (FFPE) tissue section are disclosed. The methods involve high-throughput multiplexed, quantitative IHC imaging, sequential IHC with iterative labeling, digital scanning, image coregistration and merging, and subsequent stripping of sections.
TL;DR: CRS-207 is a live, attenuated Listeria monocytogenes engineered to target mesothelin, a tumor-associated antigen over-expressed in several cancers, including MPM, an aggressive trea...
Abstract: 8558Background: CRS-207 is a live, attenuated Listeria monocytogenes engineered to target mesothelin, a tumor-associated antigen over-expressed in several cancers, including MPM, an aggressive trea
Book•
01 Jan 2016
TL;DR: This volume covers the topics presented at the 3rd International Conference on Tumor Microenvironment and Cellular Stress by an international community of researchers.
Abstract: This volume covers the topics presented at the 3rd International Conference on Tumor Microenvironment and Cellular Stress by an international community of researchers. The conference brings together scientists to discuss different cellular and animal models of tumor microenvironment study and identify common pathways that are candidates for therapeutic intervention; stimulate collaboration between groups that are more focused on elucidation of biochemical aspects of stress biology (e.g., HIF regulation) and groups that study the pathophysiological aspects of stress pathways or engaged in drug discovery; and critically evaluate novel targets for imaging or therapeutic intervention that would be of use to the tumor microenvironment community and pharmaceutical industry