bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3657: Phosphatidylserine-targeting antibodies enhance anti-tumor activity of a tumor vaccine in a HPV-induced tumor model
Authors: Weir Genevieve , Quinton Tara , Hutchins Jeff T. , Freimark Bruce D. , Stanford Marianne 
Published: July 2017

Abstract
Antibodies targeting phosphatidylserine (PS) have been shown to induce anti-tumor responses by induction of tumor-specific T cells. Based on this observation, we evaluated the responses of PS and PD-1 targeting antibody therapy to enhance anti-tumor responses of a HPV16 peptide vaccine formulated in DepoVax™ (DPX) in mice bearing HPV-transformed C3 mouse tumors. The addition of PS-targeting antibody (mch1N11) to DPX/metronomic cyclophosphamide (mCPA) immunotherapy prolonged survival in comparison to mice receiving an isotype control in combination with DPX/mCPA. When anti-PD-1 was added to mch1N11 + mCPA, there was no increase in survival. The addition of mch1N11 to DPX/mCPA immunotherapy had no effect on tumor growth or survival in the aggressive B16-F10 model. TIL analysis revealed an increase in CD8+ T cells, antigen specific CD8+ T cells and PD-1+ T cells in the tumor with mch1N11 treatment. The expression of surface markers for macrophages (CD68high, F4/80) and dendritic cells (CD11c) were also increased in the tumors of mice treated with mch1N11. RT-qPCR analysis of the tumor confirmed higher mRNA expression of T cells markers (CD8, Granzyme B, PD-1) and antigen presenting cell markers (F4/80, CD74). In the spleen, expression of cell surface markers for monocytes (CD11b) and PD-1+ T cells (CD8) were elevated in groups treated with mch1N11 in combination with anti-PD-1. Combined, these findings indicate that in this model, PS-targeting antibodies can enhance the activity of phagocytic cells involved in antigen presentation. We have found that PD-1 expression increases as anti-tumor activity increases, therefore these results also provide an indication that antibodies targeting PS enhance the anti-tumor immune response induced by DPX/mCPA therapy. The observations suggest that PS-targeting antibodies may enhance therapeutic vaccines for the treatment of cancer.
Citation Format: Genevieve Weir, Tara Quinton, Jeff T. Hutchins, Bruce D. Freimark, Marianne Stanford. Phosphatidylserine-targeting antibodies enhance anti-tumor activity of a tumor vaccine in a HPV-induced tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3657. doi:10.1158/1538-7445.AM2017-3657
Abstract 3658: Dendritic cells dictate the responsiveness of PD-L1 blockade in cancer
Authors: Mayoux Maud , Fransen Marieke F. , Roller Andreas , Matos Ines , Pulko Vesna , Karanikas Vaios , Umana Pablo , Klein Christian , Ossendorp Ferry A. , Xu Wei 
Published: July 2017

Abstract
Recent advances in cancer immunotherapies with PD-1/PD-L1 pathway blockade have transformed the way that cancer is being treated, leading to durable responses and prolonged overall survival. The general thinking is that PD-1/PD-L1 blockade reinvigorates tumor-infiltrating PD-1+ T cells with exhausted phenotypes. However, a mechanistic understanding on why only a subset of patients (10-30%) responds to checkpoint inhibition remains largely unknown, as does the exact immune mechanism of PD-1/PD-L1 blockade. Here, we discovered that PD-L1 blockade mediates anti-tumor immunity via dendritic cells. In human blood, in vitro and ex vivo dendritic cells (DCs) express both PD-1 and PD-L1, and an activation signal via TLR agonists triggers downregulation of PD-1 to empower the T cell stimulatory capability of DCs. In contrast, tolerogenic DCs remain PD-1 positive, correlating to T cell-unresponsiveness. Anti-PD-L1 Ab directly induces maturation of DCs and renders them capable of stimulating T cell proliferation. Similarly, anti-PD-L1 Ab treatment in tumor-bearing mice induces massive infiltration and activation of CD11c+ DCs in the spleen and draining lymph node, indicating that PD-1 is a negative regulator in DCs. Furthermore, ablation of DCs prior to anti-PD-L1 Ab treatment in an established MC38 tumor model in CD11c-DTR mice suggests a crucial role of DCs in mediating response to PD-L1 treatment. In support of the preclinical evidence that DCs are the primary target of anti-PD-L1 Ab, we analyzed RNA-seq data from tumor biopsies at baseline in patients with renal cell carcinoma prior to treatment with atezolizumab and found that the abundance of genes related to cross-presenting DC subsets (such as XCR1) correlates with a survival advantage in response to atezolizumab (HR=0.13, median OS is 16.2 months in patients with DC gene score &lt;50% versus NR (not reached) in those &gt;50%). In conclusion, we discovered abundance of tumor-infiltrating DCs as a novel biomarker that can predict the clinical response of PD-L1 blockade. We postulate that checkpoint inhibition directly on tumor-infiltrating DCs likely contributes to amplification of Ag-specific priming of tumor-specific T cells.
Citation Format: Maud Mayoux, Marieke F. Fransen, Andreas Roller, Ines Matos, Vesna Pulko, Vaios Karanikas, Pablo Umana, Christian Klein, Ferry A. Ossendorp, Wei Xu. Dendritic cells dictate the responsiveness of PD-L1 blockade in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2017-3658
Abstract 3662: Activation of CD40 while inhibiting IL6/STAT3 using oncolytic viruses induces mature DCs with high cytokine production but blocks PDL1 expression
Authors: Eriksson Emma , Milenova Ioanna , Wenthe Jessica , Dimberg Anna , Moreno Rafael , Ullenhag Gustav , Alemany Ramon , Loskog Angelica 
Published: July 2017

Abstract
The tumor microenvironment (TME) consists of tumor cells and stroma, including fibroblasts, blood vessels, immune cells and extracellular matrix. The TME supports tumor progression, metastasis as well as resistance to cancer therapeutics. In pancreatic cancer, the TME is dense due to overproduction of collagen and the tumor is infiltrated with suppressive myeloid cells such as M2 macrophages and myeloid suppressor cells. One key regulator of myeloid cells is CD40, a receptor expressed on a variety of cell types. CD40/CD40L signaling results in production of cytokines and chemokines by myeloid cells but also endothelial and epithelial cells to alert the immune system of immediate danger. 4-1BB is expressed by lymphocytes and dendritic cells (DCs). Stimulation via 4-1BBL drives lymphocyte expansion and regulates memory formation. IL6 signaling leads to STAT3 phosphorylation in myeloid cells and tumor cells leading to suppressive phenotypes, tumor proliferation, and angiogenesis. Further, STAT3 signaling enhances production of TGFb, which in turn leads to overexpression of collagen. We have constructed a family of oncolytic adenoviruses (LOAd) activating the CD40, 4-1BB and/or inhibiting IL6 signaling. The LOAd viruses (-, 700, 703, 713) were investigated for their capacity to activate human monocyte-derived DCs as well as their effect on pancreatic tumor cells and stroma (fibroblastic stellate cells, endothelial cells) using flow cytometry, MTS assay and ProSeek Proteomics. The LOAd viruses expressing a trimerized CD40L, 4-1BBL and/or a scFv IL6R showed efficient oncolysis of tumor cells but primary stellate cells were unaffected. However, stellate cells reduced tumor-promoting factors such as FGF5, PlGF, amphiregulin, Gal3, TGFb and collagen type I. Dendritic cells increased costimulators, cytokines as well as chemokines but PDL1 was not expressed when IL6/STAT3 was blocked. Infected endothelial cells upregulated receptors important for lymphocyte transmigration (ICAM, VCAM and E-Selectin). Taken together, our data demonstrates that it is possible to utilize oncolytic adenoviruses to spark immune activation at the same time changing biological processes via STAT3 blockade and/or CD40/4-1BB pathway activation to reduce factors that promotes tumor progression.
Citation Format: Emma Eriksson, Ioanna Milenova, Jessica Wenthe, Anna Dimberg, Rafael Moreno, Gustav Ullenhag, Ramon Alemany, Angelica Loskog. Activation of CD40 while inhibiting IL6/STAT3 using oncolytic viruses induces mature DCs with high cytokine production but blocks PDL1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3662. doi:10.1158/1538-7445.AM2017-3662
Abstract 3663: An anti-CD4 depleting antibody reverses regulatory T-cell-induced suppression of dendritic cells while preventing nonspecific CD4+ T cell responses in tumor-bearing mice
Authors: Ueha Satoshi , Ogiwara Haru , Yokochi Shoji , Ishiwata Yoshiro , Shand Francis , Hori Shohei , Kakimi Kazuhiro , Ito Satoru , Matsushima Kouji 
Published: July 2017

Abstract
Administration of an anti-CD4 depleting antibody induces tumor-specific CD8+ T cell responses in tumor-bearing mice, although the mechanisms underlying this phenomenon remain unclear. CD4+ Foxp3+ regulatory T cells (Treg) impair antigen presentation by DCs through CTLA4-mediated down-regulation of CD80/CD86. In the present study, we investigated the effects of an anti-CD4 depleting monoclonal antibody (mAb) on DC responses in the B16F10 and LLC subcutaneous tumor models, and compared these effects with those of Treg targeting therapy. Administration of anti-CD4 mAb up-regulated CD80/CD86 in tumor-infiltrating DCs, and in migrating-type but not resident-type DC subsets in the tumor-draining lymph node. The upregulation of CD80/CD86 on these DC populations was correlated with increased proliferation of tumor-specific CD8+ T cells in the tumor-draining lymph node. Anti-CD4 mAb-induced CD80/CD86 up-regulation and tumor-specific CD8+ T cell responses were remarkably higher than that induced by an anti-CD25 depleting mAb or an anti-CTLA4 blocking mAb, and were equivalent to that induced by diphtheria-toxin-induced selective depletion of Tregs in Foxp3-DTR mice. Importantly, the activation of CD4+ conventional T cells and B cells in the peripheral lymph nodes that was observed following Treg depletion was not observed following anti-CD4 mAb administration. In conclusion, anti-CD4 depleting antibody therapy is an effective way to evoke anti-tumor CD8+ T cell responses by reversing regulatory T cell-induced suppression of dendritic cells, and to reduce the risk of severe autoimmunity in cancer patients.
Citation Format: Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima. An anti-CD4 depleting antibody reverses regulatory T-cell-induced suppression of dendritic cells while preventing nonspecific CD4+ T cell responses in tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3663. doi:10.1158/1538-7445.AM2017-3663
Abstract 3670: Treatment of epithelial ovarian cancer with folate receptor (α/β) targeted chemotherapy is enhanced by CTLA-4 blockade: Learning from animal models
Authors: Lu Yingjuan , Johnson Theresa P. , Wheeler Leroy W. , Lloyd Alex M. , Cross Vicky A. , Westrick Elaine M. , Parker Nikki L. , Leamon Christopher P. 
Published: July 2017

Abstract
Epithelial ovarian cancer (EOC) remains to be the most lethal form of gynecologic malignancies despite aggressive cytoreductive surgery (i.e. debulking) followed by standard chemotherapy. The alpha folate receptor (FRα) has long been recognized as a tumor target for EOC due to its frequently intense overexpression (&gt;80%) in the most common serous histotype. Recently, the beta folate receptor (FRβ) has been discovered on tumor-associated macrophages (TAMs) which are present at various densities in solid tumors but are also found abundant in malignant ascites of EOC patients. The ascites TAMs are strongly immunosuppressive, and high TAM frequency is correlated with poor patient prognosis and treatment resistance. Respectively, tumor- and TAM-associated FRα and FRβ are both functionally active which allows for folate-targeted delivery of small-molecule drug payloads via receptor-mediated endocytosis.
Using flow cytometry, we characterized total ascites cells harvested from human IGROV1 xenograft (hFRα) and murine ID8-CL15 syngeneic (mFRα) models at the time of euthanasia. Approximately 70% of IGROV1 and 25% of ID8-Cl15 ascites TAMs (F4/80+ CD11b+) were found to express a functional mFRβ. While ascites fluids from both models caused a dramatic reduction of FRα functionality on tumor cells in-vivo and ex-vivo, FRβ expression and functionality on ascites TAMs were largely unaffected. Interestingly, in the ID8-CL15 model, the ratio of ascites CD8+ T cells to CD4+ T cells decreased as total FR functionality on TAMs increased. Two small-molecule folate-drug conjugates with different mechanisms of action showed activity in extending the survival of tumor-bearing animals. While CTLA-4 blockage alone was completely inactive in the ID8-CL15 model, a combination regimen significantly enhanced the activity of a folate conjugate carrying a potent DNA cross-linking agent. Our data suggest that EOC treatment may require a multi-pronged approach by targeting both FRα-expressing tumor cells and FRβ-expressing TAMs. In addition, immune checkpoint inhibitors may further enhance the FR-targeted therapeutics by modulating the ascites tumor microenvironment.
Citation Format: Yingjuan Lu, Theresa P. Johnson, Leroy W. Wheeler, Alex M. Lloyd, Vicky A. Cross, Elaine M. Westrick, Nikki L. Parker, Christopher P. Leamon. Treatment of epithelial ovarian cancer with folate receptor (α/β) targeted chemotherapy is enhanced by CTLA-4 blockade: Learning from animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2017-3670
Abstract 3683: Melphalan stimulates dendritic cell and CD8+ T cell expansion by inducing immunogenic cell death in melanoma cells
Authors: Johansson Junko , Kiffin Roberta , Lindnér Per , Naredi Peter , Bagge Roger Olofsson , Martner Anna 
Published: July 2017

Abstract
Background: Regional hyperthermic perfusion with the alkylating agent melphalan is a treatment option for patients with metastatic melanoma confined to the limbs or the liver. Following a single perfusion, tumors often decrease gradually in size during several months, suggesting an immune-mediated mechanism of action, in addition to the direct cytotoxic effects of melphalan. This study was designed to characterize the immunogenic effects of melphalan.
Materials and methods: We have established an in vitro model of regional hyperthermic perfusion where human melanoma cell lines are exposed to melphalan at 40oC for 1 h, thus mimicking the currently employed clinical protocol. The melphalan-exposed melanoma cells were analyzed for markers of immunogenic cell death and were co-cultured with peripheral blood mononuclear cells (PBMCs) in the presence or absence of IL-2. The number and activation status of various immune populations were analyzed by flow cytometry.
Results: Melphalan exposure triggered the expression of several immune-related markers on melanoma cells, including calreticulin, MHC class I, Hsp70 and PD-L1. Melphalan-treated, but not untreated melanoma cells, triggered an increase in dendritic cell (DC) numbers along with a dramatic expansion of CD8+ T cells in co-cultured PBMCs. The expanded CD8+ T cells showed an activated phenotype with the majority of cells belonging to the effector memory subtype.
Conclusions: Melanoma cells exposed to melphalan undergo immunogenic cell death and trigger DC expansion with subsequent expansion and activation of CD8+ T cells. We propose that these events may contribute to the anti-tumor efficacy of regional hyperthermic perfusion with melphalan in metastatic melanoma.
Citation Format: Junko Johansson, Roberta Kiffin, Per Lindnér, Peter Naredi, Roger Olofsson Bagge, Anna Martner. Melphalan stimulates dendritic cell and CD8+ T cell expansion by inducing immunogenic cell death in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3683. doi:10.1158/1538-7445.AM2017-3683
Abstract 3695: The interplay between neutrophils &It CDThe interplay between neutrophils and CD8+ cell improves survival in human colorectal cancer
Authors: Governa Valeria , Trella Emanuele , Mele Valentina , Droeser Raul , Eppenberger-Castori Serenella , Terracciano Luigi Maria , Iezzi Giandomenica , Spagnoli Giulio Cesare 
Published: July 2017

Abstract
Purpose: Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer (CRC). Still debated is the role of innate immune system. We investigated clinical relevance, phenotypes &it functional features of CRC infiltrating CD66b+ neutrophils &it their crosstalk with CD8+ T cells.
Experimental design: CD66b+ &it CD8+ cell infiltration was analyzed by immunohistochemistry on a tissue microarray including &gt;650 evaluable CRC samples. Phenotypic profiles of tissue infiltrating and peripheral blood CD66b+ cells were evaluated by flow cytometry. CD66b+/ CD8+ cells crosstalk was investigated by in vitro experiments.
Results: CD66b+ cell infiltration in CRC is significantly associated with increased survival. Interestingly, neutrophils frequently co-localize with CD8+ T cells in CRC. Functional studies indicate that although neutrophils are devoid of direct antitumor potential, co-culture with peripheral blood or tumor associated neutrophils (TANs) enhances CD8+ T cell activation, proliferation and cytokine release induced by suboptimal concentrations of anti-CD3 monoclonal antibody (mAb). Moreover, under optimal activation conditions, CD8+ cells initially stimulated in the presence of CD66b+ cells show decreased expression of PD-1 “exhaustion” marker and are significantly less susceptible to apoptosis induced by T- cell receptor triggered re-stimulation. Importantly, combined tumor infiltration by CD66b+ and CD8+ T lymphocytes is associated with significantly better prognosis, as compared to CD8+ T cell infiltration alone.
Conclusions: Neutrophils enhance the responsiveness of CD8+ T cells to TCR triggering. Accordingly, infiltration by neutrophils enhances the prognostic significance of CRC infiltration by CD8+ T cells, suggesting that they might effectively promote antitumor immunity.
Note: This abstract was not presented at the meeting.
Citation Format: Valeria Governa, Emanuele Trella, Valentina Mele, Raul Droeser, Serenella Eppenberger-Castori, Luigi Maria Terracciano, Giandomenica Iezzi, Giulio Cesare Spagnoli. The interplay between neutrophils &It CDThe interplay between neutrophils and CD8+ cell improves survival in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3695. doi:10.1158/1538-7445.AM2017-3695
Abstract 3697: The impact of HER3 signaling mediated PD-L1 regulation in triple negative breast cancer
Authors: Yamaguchi Ayane , Suzuki Eiji , Kawaguchi Kosuke , Nishie Mariko , Tsuda Moe , Kotake Takeshi , Toi Masakazu 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) is still difficult to treat partly because of lacking specific target. Although 50-70% of TNBC expresses EGFR, it is less sensitive to the treatment of EGFR inhibition for TNBC as compared to the efficacy of HER2 inhibition for HER2-positive breast cancer. Several phase II study on EGFR blockade treatment has been reported, however it has not applied in a clinical setting yet. It was reported that residual tumors after treatment with EGFR-targeted antibodies showed increased HER3 abundance leading to EGFR/HER3 receptor dimerization. The signals of HER3/EGFR dimerization to PI3K/AKT/mTOR pathways are thought to be involved in cancer survival, proliferation and also up-regulation of PD-L1 expression. Thus, we hypothesized that up-regulation of HER3 signal caused by anti-cancer treatment might induce PD-L1 expression and inhibit host anti-tumor immunity. In this study, we tested the relationships between HER3 signal and PD-L1 expression by using three basal-like breast cancer cell line; MDA-MB-231, HCC70, and MDA-MB-468. MDA-MB-231 is HER3-negative, and HCC70 and MDA-MB-468 are HER3-positive cell lines. We added neureglin 1 (NRG1: HER3 ligand) to those three cell lines and analyzed PD-L1 expression of protein by flowcytometry and mRNA by qRT-PCR. Both protein and mRNA level of PD-L1 on HCC70 and MDA-MB-468 treated with NRG1 are increased as compared with those without NRG1 while there was no change of PD-L1 expression of MDA-MB-231 either with or without NRG1. In order to confirm the significance of potential treatment target of HER3, we evaluated HER3 expression in biopsy samples by immunohistochemistry before neoadjuvant chemotherapy (NAC) including all phenotypes. Thirteen pathological complete response (pCR) cases after NAC and 6 non pCR cases were included. We scored the HER3 stainability from 0 to 3 and found that non pCR cases showed significantly higher HER3 score than pCR cases (84.6% and 33% respectively, p=0.0149).
Although further study is needed, these results suggest that HER3 signal possibly regulates PD-L1 expression in HER3-positive basal-like breast cancer and treatment with anti-HER3 targeting therapy combination with an immune checkpoint inhibition therapy for HER3 positive NAC resistant patients might be warranted.
Note: This abstract was not presented at the meeting.
Citation Format: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Masakazu Toi. The impact of HER3 signaling mediated PD-L1 regulation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3697. doi:10.1158/1538-7445.AM2017-3697