bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1700: Metabolic adaptations confer immunotherapy resistance in melanoma
Authors: Jaiswal Ashvin R. , Pudakalakatti Shivanand , Prasanta Dutta , Liu Arthur , Bartkowiak Todd , Ager Casey , Davies Michael A. , Davis Richard E. , Wargo Jennifer , Bhattacharya Pratip K. , Hong David S. , Curran Michael A. 
Published: August 2018

Abstract
Background: Despite the success of T-cell checkpoint blockade antibodies in treating an array of cancers, the majority of patients still fail to respond to these therapies, or respond transiently and then relapse. The molecular mechanisms that drive lack of response to checkpoint blockade, whether pre-existing or evolved on therapy, remain unclear.
Materials and Methods: To address this critical gap in clinical knowledge, we established a mouse model of melanoma designed to elucidate the molecular mechanisms underlying immunotherapy resistance. Through multiple in vivo passages, we selected a B16 melanoma tumor line that evolved complete resistance to combination blockade of CTLA-4, PD-1, and PD-L1, which cures ~75% of mice of the parental tumor. Using gene expression analysis, proteomics, and immunogenomics, we determined the adaptations engaged by this melanoma to become completely immunotherapy resistant. NMR spectroscopy, Seahorse XF Analysis, flow cytometry, confocal microscopy and Western blot analysis provided further insight into the mechanisms driving checkpoint blockade resistance.
Results: Acquisition of immunotherapy resistance by these melanomas was driven by acquisition of a hypermetabolic state through coordinate upregulation of both glycolysis and oxidative phosphorylation (OxPhos). Depletion of essential nutrients from the tumor microenvironment by these resistant tumors functionally compromises infiltrating T cells to an extent that cannot be rescued by even triple checkpoint blockade. The glycolysis and OxPhos-associated genes most highly induced by these resistant melanomas were capable of conferring enhanced resistance to checkpoint blockade when reintroduced monogenically into the parental tumor. We have validated upregulation of these pathways in a unique cohort of melanoma patients who failed dual checkpoint blockade. Additionally, we employed a novel MRI imaging technique to visualize metabolic changes acquired by resistant tumors in live mice. Clinical application of this technique could provide a much-needed noninvasive tool to predict immunotherapeutic sensitivity of patient cancers.
Conclusion: Acquisition of a hypermetabolic state by melanoma tumor cells cripples T cells in the microenvironment and confers complete resistance to checkpoint blockade.
Citation Format: Ashvin R. Jaiswal, Shivanand Pudakalakatti, Dutta Prasanta, Arthur Liu, Todd Bartkowiak, Casey Ager, Michael A. Davies, Richard E. Davis, Jennifer Wargo, Pratip K. Bhattacharya, David S. Hong, Michael A. Curran. Metabolic adaptations confer immunotherapy resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1700.
Abstract 1705: Systemic analysis of innate responses to anti-PD1/PD-L1 treatment in a melanoma model
Authors: Gassen Rodrigo , Welm Alana , Bonorino Cristina 
Published: August 2018

Abstract
Response to anti-PD1 therapy for tumors is often thought to target T cells, directly and exclusively. However, while some patients, even with metastasis, respond completely, most patients do not respond to treatment as predicted. The mechanisms of response ad resistance to anti-PD-1 therapy need to be elucidated, in order to optimize treatment and prevent unnecessary adverse effects. Most innate cells, especially in tumor bearing individuals, express PD-1, not only in the tumor microenvironment, but systemically. Among those are macrophages and dendritic cells. The implications of PD-1 expression by these cells in their immune function are still unknown, and so are the signaling pathways activated by agonists or antagonists of this receptor. Although recent data suggest that PD-1+ tumor associated macrophages (TAMs) promote advanced tumor growth, little is known of the kinetics of PD-1 expression by innate cells during tumor progression. Using an immunocompetent murine melanoma model, we characterized PD-1 and PD-L1 expression in different innate cells, in lymphoid organs, blood, and tumor microenvironment. In NSG mice, using PDX grafts of triple negative breast cancers, we determined that such expression is independent of lymphocytes and NK cells. Treatment with anti-PD-1 mobilized an early (7 days) wave of DC migration that can be seen in the blood, preceding a CD4+ T cell mobilization that peaked ad day 14 after treatment. These early responses correlated with CD8+ T cell infiltration to the tumor microenvironment as well as tumor regression. PD-1 expression and migration in the blood was different among the DC subpopulations, and anti-PD-1 treatment enhanced survival as well as activation of dendritic cells. These findings are relevant to understanding the different outcomes of immunotherapy with anti-PD-1 and anti-PD-L1.
Citation Format: Rodrigo Gassen, Alana Welm, Cristina Bonorino. Systemic analysis of innate responses to anti-PD1/PD-L1 treatment in a melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1705.
Abstract 1706: Inhibition of fibulin-3 reverses macrophage polarization in glioblastoma and increases anti-tumor inflammatory responses
Authors: Longo Sharon L. , Behera Prajna , Viapiano Mariano S. , Nandhu Mohan Sobhana 
Published: August 2018

Abstract
Glioblastomas (GBMs) are the most common primary tumors of the Central Nervous System and one of the most aggressive and difficult to treat forms of cancer. Our laboratory was the first to identify the extracellular protein fibulin-3 (EFEMP1) in GBMs and demonstrate the pro-tumoral functions of this protein in solid tumors. We have recently developed a function-blocking antibody ("mAb428.2") against fibulin-3, which inhibits the enhancing effect of this protein on ADAM17 activity and NFkB signaling (Nandhu et al., Clin Cancer Res, 2017). Using mAb428.2 we observed a significant anti-tumor effect and prolongation of survival in nude mice carrying patient-derived GBM xenografts implanted subQ or intracranially (antibody treatment: 8x 30 mg/kg, q24h, IV). Interestingly, reduction of tumor growth during mAb428.2 treatment was accompanied with significant tumor necrosis and increased infiltration of Iba1-positive tumor-associated macrophages (TAMs) both in subQ and orthotopic tumors. Remarkably, TAMs in mAb428.2-treated GBMs showed very low co-expression of Arginase-I, a bona-fide marker of M2 ("tumor promoting") TAM polarization. Further analysis of mouse-specific gene expression in the tumor mass and in recovered macrophages (CD11b-positive cells) showed that TAMs in mAb428.2-treated GBMs had significantly increased expression of inflammatory cytokines (IFN-gamma, IL-1b, IL-10) and downregulation of M2 markers (CD163, CD206, ARG1), suggesting that our anti-fibulin-3 treatment prevented the expected M2 polarization of TAMs. Accordingly, mAb428.2-treated tumors showed drastically decreased expression of CSF-1a, an M2-inducing cytokine that may be regulated by fibulin-3. Co-culture experiments of PMA-activated U937 macrophages with GBM stem-like cells did not affect tumor cell viability when a control IgG1 was added to the cultures. However, addition of mAb428.2 caused significant decrease of GBM cell viability, suggesting that anti-fibulin-3 treatment enables TAMs to attack tumor cells. Taken together, our results strongly suggest that anti-fibulin-3 and possibly other anti-ECM approaches may induce a marked inflammatory reaction driven by innate immune cells, potentiating anti-tumor therapy.
Citation Format: Sharon L. Longo, Prajna Behera, Mariano S. Viapiano, Mohan Sobhana Nandhu. Inhibition of fibulin-3 reverses macrophage polarization in glioblastoma and increases anti-tumor inflammatory responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1706.
Abstract 1713: Immunomodulatory effect of statins on Tregs within human colorectal cancer is determined by the stage of disease
Authors: Al-Husein Belal 
Published: August 2018

Abstract
Colorectal cancer (CRC) is a public health problem worldwide and in Jordan. Statins are best seller cholesterol lowering agents. Beyond their cholesterol-lowering effects, statins use has been reported to reduce the risk of several malignances including CRC. This study aimed to assess the effect of statins on CRC risk by studying cellular infiltration of Tregs into CRC tissues and their effect on Transforming growth factor beta 1 (TGF-β1) level and angiogenesis. A total 47 specimens (25 statins users, and 22 statins nonusers) of CRC were used. Immunohistochemical analysis was performed to study Tregs infiltration by studying their specific marker fork head transcription factor (FOXP3), and angiogenesis by studying CD31 positive blood vessels. TGF-β level was measured using commercial ELISA kits. Results revealed that in case of statins use was associated with more Tregs infiltration, more angiogenesis but no difference in TGF-β1 content in tumor tissue. When further categorized analysis according to stage of disease, angiogenesis effect was more pronounced in early disease and wasn't significant in advanced disease.In addition, more Tregs infiltration was significantly noticed in advanced disease but not in early disease. Same stage-dependence wasn't notices with TGF-β1. Since statins are associated with reduced risk of death in colorectal cancer patients, we could suggest some immunologic mechanism for that. Tregs infiltration into tumor and reduction of inflammation at tumor site might reduce cancer aggressiveness in advanced disease. In advanced disease, however, reduction of angiogenesis would be the cause of tumor aggressiveness. These results suggest that statins might be used in prophylaxis or treatment of CRC. Further studies are needed to evaluate the effect of various types and doses of statins.
Citation Format: Belal Al-Husein. Immunomodulatory effect of statins on Tregs within human colorectal cancer is determined by the stage of disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1713.
Abstract 172: Collagen increases tumorigenic characteristics of papillary thyroid cancer cells harboring BRAFV600Emutations
Authors: Sharabura Anna , Jenkins Jonathan , MacDonald Laura 
Published: August 2018

Abstract
Thyroid cancer is the most common endocrine cancer, and incidence is increasing worldwide. Thyroid cancer can be classified as either well differentiated or poorly differentiated. Of well-differentiated thyroid cancers, papillary thyroid cancer is most common, and is associated with activating BRAF mutations. While our understanding of the genetic basis for thyroid cancer is fairly extensive, less is known about how the tumor microenvironment alters characteristics of tumor cells. Recently, Jolly and others reported that papillary thyroid tumors derived from cells harboring BRAFV600E mutations and PTEN deletions are enriched with fibrillar collagen. Notably, overexpression of collagen was also associated with decreased survival and worse overall prognosis in patient samples. In this study, we investigated whether growth on collagen enhanced tumorigenic characteristics of papillary thyroid cancer cell lines with BRAFV600E mutations. Three distinct cell lines derived from mouse papillary thyroid cancer tumors were grown in the presence and absence of collagen and assessed for changes in morphology, proliferation, and drug resistance. Interestingly, our results suggest that growth on collagen contributes to a more mesenchymal morphology, increased proliferation, and decreased sensitivity to chemotherapy drugs. These and other results implicate an important role for collagen in the progression of thyroid cancer.
Citation Format: Anna Sharabura, Jonathan Jenkins, Laura MacDonald. Collagen increases tumorigenic characteristics of papillary thyroid cancer cells harboring BRAFV600Emutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 172.
Abstract 1730: A translational platform using primary human immune cells in vitro, syngeneic and humanized models in vivo to support and advance immuno-oncology drug discovery
Authors: O'Rourke Martin , Roman Shilina , Salmon Gary , Waddell Ian , Schueler Julia , Wood Edgar 
Published: August 2018

Abstract
Charles River Laboratories (CRL) has established a powerful translational immuno-oncology platform with the capability of progressing biologics or small-molecule modulators of immune response from in vitro to in vivo assays using human and mouse variants of current checkpoint inhibitors and small molecules. Utilizing a blood donor panel, our in vitro platform includes primary human immune cell assays that profile T-cell activation, T cell mediated-cancer cell kill, expansion of T-cell populations, mixed lymphocyte reactions (MLR), T-cell invasion, and antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The platform is currently being expanded to determine the effect of activated immune cell populations on tumor cell spheroid cultures. It has been validated with standard-of-care chemotherapeutics, including anti-CTLA4, anti-PD1 and a selection of small-molecule inhibitors of targets known to modulate immune responses including IDO inhibitors. Ex vivo analysis of activated mouse splenocyte response to checkpoint inhibitors, measured as cytokine release, and modulation of immune cell populations, as determined by flow cytometry, supports the translation of important compounds from the bench to preclinical models. Syngeneic mouse tumor models have frequently been used to profile immune responses in tumors; CRL has optimized and profiled existing checkpoint inhibitors to support immuno-oncology drug discovery using mouse and rat antibody variants of anti-CTLA4 and anti-PD1. To confirm the translational development of our platform in human tissue, CRL has developed and optimized humanized mouse models using subcutaneous implanted patient-derived xenografts (PDX) with human engraftment via CD34+ haematopoeitic stem cells in NOG mice, which were treated with anti-CTLA4 and anti-PD1. Infiltration of human immune cells and PDL-1 expression was detected by flow cytometry (FC) and immunohistochemistry (IHC) in hematopoietic organs and tumor tissue, supporting the initial in vitro response in primary immune cells. Here we present a screening platform, validated with standard-of-care chemotherapeutics, which will support translation of compounds from in vitro primary immune cell assays to modulation of mouse immune cell population in spleen and tumors, resulting in efficacy and tumor immune cell activation in humanized mouse models.
Citation Format: Martin O'Rourke, Shilina Roman, Gary Salmon, Ian Waddell, Julia Schueler, Edgar Wood. A translational platform using primary human immune cells in vitro, syngeneic and humanized models in vivo to support and advance immuno-oncology drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1730.
Abstract 1732: Gp96-Ig/costimulator combination platform improves T cell priming and enhances immunity, memory, and tumor elimination
Authors: Giffin Louise , Gonzalez Louis , Rose Jason , Hutchins Jeff 
Published: August 2018

Abstract
In this study, we report that addition of checkpoint inhibition and T cell costimulators into the Heat Biologics gp96-Ig-based vaccine platform elicits stronger antigen-specific CD8+ T cell activation and expansion, stimulates memory precursor cell activation, and enhances rejection of murine tumors. Despite the dramatic successes of checkpoint inhibitors in limited populations of cancer patients, 60-90% of patients are still failing to respond to these therapies. It is widely believed that approaches such as ours that target multiple facets of the immune system, including combinations with checkpoint inhibition and costimulator agonism, will be required to improve patient outcomes. Heat Biologics' first-generation ImPACT vaccine is a cell-based therapy that utilizes representative tumor cell lines expressing the antigen chaperone, gp96-Ig, to efficiently prime antigen-specific CD8+ T cells. Heat recently developed a next generation vaccine called ComPACT (COMbination Pan-Antigen Cytotoxic Therapy) that incorporates expression of a T cell costimulator (OX40L-Ig) and gp96-Ig within a single vaccine cell line. In multiple murine tumor and tumor-naive models, ComPACT elicits more potent activation of antigen-specific T cells as well as expansion of CD127+KLRG1- memory precursor cells, leading to a detectable memory response. Furthermore, ComPACT lacks the toxic systemic inflammatory cytokine production and proliferation of non-specific CD4+ T cells and Tregs observed with systemic administration of OX40 agonist antibodies. ComPACT also leads to high frequencies of IFNγ+, TNFα+, granzyme B+ and IL-2+ antigen-specific CD8+ T cells in mice at both priming and boosting, which increases rejection of established murine melanoma (B16.F10) and colon cancer (CT26) tumors and increased overall survival. Here, we have further assessed ImPACT and ComPACT-OX40L in combination with the anti-PD1 checkpoint inhibitor and with expression of an additional cell-secreted T cell costimulator, TL1A-Ig. In various murine models we show that these treatments synergize effectively to amplify antigen-specific T cells, program a functional memory response, and eliminate tumors. The combination of ComPACT-OX40L/TL1A with αPD1 or αPD-L1 may therefore translate into an efficacious approach to treat human cancers.
Citation Format: Louise Giffin, Louis Gonzalez, Jason Rose, Jeff Hutchins. Gp96-Ig/costimulator combination platform improves T cell priming and enhances immunity, memory, and tumor elimination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1732.
Abstract 1737: Efficacy of immunotherapy is attenuated with age in triple-negative breast cancer
Authors: McAllister Sandra S. , Sceneay Jaclyn , Laszewski Tyler , DeCristo Molly , Ubellacker Jessalyn , Wilson Kristin , Qin Yuanbo , Hutchinson John 
Published: August 2018

Abstract
Age is associated with increasing immune dysfunction that includes significant changes to both the innate and adaptive immune responses. These age-related changes could present limitations to the application of immunotherapy in breast cancer, as over 50% of patients are over 60 years old at diagnosis. Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, but remains the only subtype that lacks any type of targeted therapy. Early results from clinical trials of anti-PD-1 therapy in metastatic TNBC patients have shown promise, with approximately 20% of patients demonstrating a partial or complete response. While TNBC incidence is similar in young and old patients, differences in disease progression and outcome with age suggest that treatment needs to be tailored to both age as well as breast cancer subtype. It is not known whether age impacts response to immunotherapy, particularly checkpoint blockade, in breast cancer. Using multiple preclinical models of age-dependent TNBC, we found that aged mice had significantly reduced ability to respond to either anti-PD-L1 or anti-CTLA4. Old mice showed decreased numbers of circulating CD4-positive and CD8-positive T cells, as well as NK cells. Furthermore, PD-1 expression was increased on these populations relative to young mice, suggesting increased immune cell exhaustion with age. The old mice also demonstrated increased central and effector memory T cells, but decreased naive T cells compared to young mice, consistent with reports from clinical studies of aged individuals. These findings suggest decreased ability to respond to neoantigens with age. Importantly, using high-content flow cytometric analyses and RNA-seq, we defined cellular and molecular mechanisms that correlate with response in young mice that are attenuated or lacking in old mice. Many of the differentially expressed genes that defined response to anti-CTLA4 in young mice and resistance to treatment in the old mice were also predictors of response to immunotherapy in cancer patients. Our data suggested novel combination therapies that, when combined with checkpoint blockade, improved responses and survival in old mice with TNBC. Our findings should suggest age-stratified treatments to ensure that TNBC patients see the most benefit possible and prevent overtreatment with futile and harsh chemotherapies.
Citation Format: Sandra S. McAllister, Jaclyn Sceneay, Tyler Laszewski, Molly DeCristo, Jessalyn Ubellacker, Kristin Wilson, Yuanbo Qin, John Hutchinson. Efficacy of immunotherapy is attenuated with age in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1737.
Abstract 1750: Inducing therapeutic lymphangiogenesis for potentiating cancer immunotherapy in melanoma
Authors: Potin Lambert , Maillat Lea , Briquez Priscilla S. , Hubbell Jeffrey A. , Swartz Melody A. 
Published: August 2018

Abstract
Tumor-associated lymphangiogenesis is well known to promote metastasis and to correlate with poor prognosis in melanoma and other cancers, yet its functional roles in antitumor immunity had remained largely unexplored. In a recent study, we investigated the role of the vascular endothelial growth factor C (VEGF-C)—the main driver of lymphangiogenesis—in regulating antitumor immune response. We showed that in the B16 F10 injectable melanoma model, VEGF-C inhibition prevented T cells from infiltrating the tumor and reduced the efficacy of immunotherapies. Here, we sought to extend this concept to exploit the immunologic benefits of VEGF-C for therapeutic applications. We engineered a VEGF-C variant with an extracellular matrix-binding domain (MB-VEGF-C) allowing retention into the microenvironment after intratumoral injection. MB-VEGF-C induced increased lymphatic vasculature in tumors without reducing tumor growth rate. In an autochthonous melanoma model with reduced immune infiltrates, MB-VEGF-C intratumoral injections promoted the infiltration of cross-presenting DCs, as well as CD8+ and CD4+ T cells. Crucially, in these tumors that are normally unresponsive to immune checkpoint blockade (ICB), we could restore the responsiveness to ICB by delivering MB-VEGF-C together with immune adjuvants. Taken together, our findings suggest that VEGF-C and tumor-associated lymphangiogenesis, albeit promoting metastasis, can also be exploited to promote a T cell-inflamed microenvironment and to subsequently potentiate immunotherapies.
Citation Format: Lambert Potin, Lea Maillat, Priscilla S. Briquez, Jeffrey A. Hubbell, Melody A. Swartz. Inducing therapeutic lymphangiogenesis for potentiating cancer immunotherapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1750.