bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3763: IDO vaccine enhances antigen-specific anti-tumor effects by reducing IDO-expressing antigen presenting cells and MDSCs
Authors: Nandre Rahul , Verma Vivek , Gaur Pankaj , Vir Pooja , Wang Hua , Kang Baolin , Pedersen Ayako Wakatsuki , Zocca Mai-Britt , Andersen Mads Hald , Gupta Seema , Khleif Samir 
Published: August 2018

Abstract
Tumors evade immune surveillance using several mechanisms such as induction of regulatory T-cells (Tregs) and upregulation of indolemine-2,3-dioxygenase (IDO) enzyme. IDO is an intracellular enzyme that mediates its immunosuppressive effects by depleting tryptophan leading to accumulation of kynurenine and in turn reducing the proliferation of effector cells while activating Tregs. IDO is expressed by several suppressive immune cells including Tregs, suppressive antigen presenting cells (APCs), as well as by tumor cells. These immunosuppressive effects of IDO make it an attractive target for cancer immunotherapy, including a target for vaccine therapy. To test the anti-tumor immune effect of IDO vaccine, we evaluated the anti-tumor effect of an IDO-derived MHC I restricted peptide (IDO-pep) vaccine in the low IDO-expressing (TC-1) and high IDO-expressing B16 (melanoma) mouse tumor models. For this, mice were treated with three doses of IDO-peptides in combination with the respective tumor-specific vaccines (E7 for TC-1 and gp100 for B16) at an interval of seven days, followed by assessment of tumor growth and mice survival. We observed a significant delay in the tumor growth and prolonged survival in both tumor models when IDO vaccine was combined with tumor-specific antigen vaccine. We found that tumor-infiltration of antigen-specific CD8+ T-cells was significantly enhanced following the addition of IDO vaccine. Furthermore, while CD4+ T-cells increased in the tumor microenvironment (TME), there was a significant reduction in the numbers of Treg cells. We also found a significant reduction in the numbers of IDO-expressing myeloid-derived suppressor cells (MDSCs), dendritic cells as well as macrophages out of the total CD45+CD11b+ myeloid cells in the TME after the administration of IDO-pep in combination with tumor antigen-specific vaccine. In conclusion, our findings suggest that IDO-pep vaccine enhances the specific anti-tumor immune response by increasing the tumor antigen-specific effector T-cell infiltration in the TME through inhibition of immune suppressive cells. These results also suggest that MHC I restricted IDO peptide treatment is a promising strategy to improve cancer immunotherapy.
Citation Format: Rahul Nandre, Vivek Verma, Pankaj Gaur, Pooja Vir, Hua Wang, Baolin Kang, Ayako Wakatsuki Pedersen, Mai-Britt Zocca, Mads Hald Andersen, Seema Gupta, Samir Khleif. IDO vaccine enhances antigen-specific anti-tumor effects by reducing IDO-expressing antigen presenting cells and MDSCs [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 3763.
Abstract 3773: RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody
Authors: Gaur Pankaj , Verma Vivek , Nandre Rahul , Vir Pooja , Wang Hua , Kang Baolin , Carter Laura , Hu Xiao , Liu Xikui , Gupta Seema , Khleif Samir 
Published: August 2018

Abstract
Combination immunotherapy strategies are being developed to improve the clinical outcome in cancer patients. T-cell costimulation through OX40 has been shown to promote expansion and proliferation of effector T-cells leading to enhanced effector functions, memory generation and immune inflammatory antitumor responses. However, treatment with anti-OX40 as a single agent has not led to major positive clinical outcomes. Therefore, anti-OX40 is an ideal candidate for combination immunotherapy. In preclinical models, we have recently shown that combining anti-PD-1 concurrently with anti-OX40 negates the effects of agonist anti-OX40, making identification of combination partners crucial for antitumor therapy. RORγt, a master transcription factor, is known to drive Type 17 T-cell differentiation. Synthetic, small-molecule RORγ agonists have been shown to enhance Type 17 T-cell effector functions and survival, decrease immune suppressive mechanisms and modulate expression of a number of costimulatory and coinhibitory molecules. We hypothesized that combining RORγ agonist could enhance the antitumor effects of anti-OX40. Using a murine model where vaccine is used to prime the immune system, we assessed the effects of anti-OX40 antibody combined with a RORγ agonist (LYC-54143) on growth of established tumors and survival. We found that the combined treatment resulted in a significantly delayed tumor growth and prolonged mice survival. Analysis of the tumor microenvironment revealed that combination therapy significantly increased the numbers of total CD4+ T-cells including RORγt+ and highly activated INFγ+ cells, decreasing Treg numbers. Moreover, we found that RORγ agonist resulted in an increase in the numbers of total, antigen-specific, granzyme B+, and IFNγ+ CD8+ T-cells in the TME. These results show that inducing Th17 cells within the TME produces better anti-OX40 effect, suggesting that agonist anti-OX40 and RORγ agonist treatment is a novel potent combination for cancer immunotherapy.
Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody [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 3773.
Abstract 3774: BGB324, a selective small-molecule inhibitor of receptor tyrosine kinase AXL, targets tumor immune suppression and enhances immune checkpoint inhibitor efficacy
Authors: Davidsen Kjersti , Wnuk-Lipinska Katarzyna , Du Wenting , Blø Magnus , Engelsen Agnete , Terry Stephane , D´mello Stacey , Lie Maria , Kang Jing , Hodneland Linn , Bougnaud Sebastien , Aguilera Kristina , Straume Oddbjørn , Chouaib Salem , Brekken Rolf A. , Gausdal Gro , Lorens James B. 
Published: August 2018

Abstract
The AXL receptor tyrosine kinase is associated with poor overall survival in a wide spectrum of cancers. AXL signaling is important for tumor cell plasticity related to epithelial-to-mesenchymal transition (EMT), immune escape and intrinsic resistance to cytotoxic lymphocytes. AXL is expressed on several cells associated with the tumor immune microenvironment, including natural killer (NK) cells, dendritic cells and a subset of tumor-associated myeloid cells. AXL signaling enhances secretion of immune-suppressive cytokines from innate immune cells that limit antitumor immunity. Hence AXL resides uniquely at the nexus between tumor and microenvironmental antitumor immune suppression mechanisms. BGB324, a selective clinical-stage small-molecule Axl kinase inhibitor, is currently being evaluated in combination with pembrolizumab in three phase II clinical trials in patients with TNBC (NCT03184558), NSCLC (NCT03184571) and melanoma (NCT02872259). We show that BGB324 targets immune suppression mechanisms in the tumor microenvironment that improve immunotherapy in different murine tumor models. BGB324 treatment reduces myeloid-derived suppressor cells and tumor-associated macrophages, and lowers CCL11, IL-7, IL-1β, and IL-6 in murine pancreatic cancer models. This altered immune landscape is associated with increased tumor infiltration of NK and CD8+ T cells and enhanced therapy responses. Further, BGB324 targets tumor intrinsic immune resistance and enhances human CD8+ T cell and NK-cell mediated NSCLC tumor cell lysis. We are currently using high-dimensional mass cytometry analysis (CyTOF) to map adaptive Axl-dependent immune suppression during immune checkpoint blockade. Collectively these results highlight a prominent function for AXL in resistance to immune therapy and support continued clinical translation of combining BGB324 with immune checkpoint inhibitors to improve cancer treatment.
Citation Format: Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Wenting Du, Magnus Blø, Agnete Engelsen, Stephane Terry, Stacey D´mello, Maria Lie, Jing Kang, Linn Hodneland, Sebastien Bougnaud, Kristina Aguilera, Oddbjørn Straume, Salem Chouaib, Rolf A. Brekken, Gro Gausdal, James B. Lorens. BGB324, a selective small-molecule inhibitor of receptor tyrosine kinase AXL, targets tumor immune suppression and enhances immune checkpoint inhibitor efficacy [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 3774.
Abstract 3784: Intraoperative changes of low density granulocyte (LDG) in gastrointestinal cancer surgery
Authors: Kumagai Yuko 
Published: August 2018

Abstract
Background: Low density granulocytes (LDG) have been shown to be increased in peripheral blood of autoimmune disease, severe sepsis and cancer. In this study, we examined the frequency and function of the LDG in patients who received abdominal surgery for gastrointestinal malignancy. Method: In 57 patients who received laparotomy due to the gastrointestinal cancer ( 5 esophageal, 25 gastric , 27 colorectal cancer), peripheral blood was collected before and after operative procedure in operation room. After Ficoll-Hypaque centrifugation, intermediate layer which consists mainly of mononuclear cells was collected and immunestained with mAbs to CD66b, CD45 as well as 7AAD and their expressions were examined with flow cytometer. CD66b(+) CD45(+) cells were defined as LDG and the ratios of LDG in total CD45(+) leukocytes were calculated in 7AAD(-) live cell fraction. Next, CD66b(+) LDG and CD66b(-) mononuclear cells were separated with MACS method, and LDG were cultured and examined for extracellular traps (NETs) formation in vitro. Finally, CD66b(-) mononuclear cells were cultured on anti-CD3 mAb coated plate with or without autologous LDG, and proliferation of T lymphocytes was examined with CFSE dilution method. Results: The ratio of the LDG is low (median= 1.14%, 0.62 ~1.66%, n=57) at a beginning of surgery. In contrast, the ratio was markedly increased (median= 8.10%, 5.91~10.3%, n=57, p&lt;0.001) at the end of surgery. The ratio of postoperative LDG showed significant correlation with operation time and positive trend with intraoperative bleeding. The LDG showed relatively week expression of CD11b and CD66b, but highly expressed in IL8 receptor and CD62L, suggesting immature LDG. The short-term culture of the LDG produced massive SYTOX-positive web like stricture which was characteristic for NETs. The mixture of tumor cells on the LDG culture demonstrated that many tumor cells were trapped in the NETs within 5 min incubation and vigorously grew thereafter. Finally, addition of the LDG on mononuclear cell culture strongly suppressed the anti-CD3 stimulated T cell division. Conclusion: LDG with immature phenotype increase in circulating blood of the patients who underwent gastrointestinal cancer surgery, probably due to the surgical stress. The LDG produce NETs which may efficiently trap circulating tumor cells, and can inhibit T lymphocyte mediated-immune reaction. Thus, the LDG provide tumor permissive microenvironment in target organ and have supportive roles on the development of postoperative hematogenous metastasis in gastrointestinal cancer.
Citation Format: Yuko Kumagai. Intraoperative changes of low density granulocyte (LDG) in gastrointestinal cancer surgery [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 3784.
Abstract 3786: ILC-k: Human innate lymphoid cells displaying unique metabolic features and KIR-independent cytotoxicity, impaired in acute myeloid leukemia
Authors: Salomé Bérengère , Gomez-Cadena Alejandra , Loyon-Bonato Romain , Suffiotti Madeleine , Salvestrini Valentina , Curti Antonio , Tentorio Paolo , Mavilio Domenico , Riether Carsten , Ochsenbein Adrian , Marcenaro Emanuela , Gfeller David , Romero Pedro , Trabanelli Sara , Jandus Camilla 
Published: August 2018

Abstract
Innate Lymphoid Cells (ILCs) are a recently identified family of lymphocytes, divided into 3 different groups that mirror the functional specialization of helper CD4 T cells. However, it is now clear that the spectrum of ILC diversity is much broader than originally appreciated. ILCs have been shown to play important roles in inflammatory and autoimmune diseases, and their involvement in anti-tumor responses has also recently been evidenced by us and others. Here, we report on the identification of a previously undescribed human ILC subset, named hereafter “ILC-killer” (ILC-k), characterized by a Lineage negative, CD127+ cKIT- CRTh2- CD56+ phenotype, thus being distinct from conventional helper ILCs, e.g ILC1 (CD56-), ILC2 (CRTh2) and ILC3 (cKIT+). Transcriptomic profiling of ex-vivo highly pure ILC-k, conventional ILC subsets and conventional Natural Killer (NK) cell subsets showed closeness between ILC-k, ILC3 and CD56bright NK cells. However, ILC-k display a specific metabolism (low glucose uptake, high mitochondrial activity) and cytotoxic gene signature, also confirmed at protein level. By their functional evaluation, ILC-k showed specific ability to kill tumor cell lines in a KIR-independent, but NKp30- and Trail-dependent manner. Their relative frequency is decreased and both their metabolic fitness and cytotoxic potential are impaired in Acute Myeloid Leukemia (AML) patients at diagnosis (N=51). Upon remission, ILC frequencies and functions are restored to normal levels. Overall, we identified cytotoxic ILCs, distinct from conventional NK cells, that are functionally impaired in AML. Given their KIR-independence, ILC-k might represent promising therapeutic candidates to improve NK-cell based immunotherapy, that currently necessitates KIR-HLA mismatch between donor and recipient for full efficiency.
Citation Format: Bérengère Salomé, Alejandra Gomez-Cadena, Romain Loyon-Bonato, Madeleine Suffiotti, Valentina Salvestrini, Antonio Curti, Paolo Tentorio, Domenico Mavilio, Carsten Riether, Adrian Ochsenbein, Emanuela Marcenaro, David Gfeller, Pedro Romero, Sara Trabanelli, Camilla Jandus. ILC-k: Human innate lymphoid cells displaying unique metabolic features and KIR-independent cytotoxicity, impaired in acute myeloid leukemia [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 3786.
Abstract 3796: Substrate specificity of human kallikrein-related peptidase 2 (KLK2) towards beta chain of interleukin-10 receptor
Authors: Neto Luiz J. , Juliano Maria A. , Oliveira Juliana R. 
Published: August 2018

Abstract
The kallikrein-related peptidases (KLKs) comprise a family of 15 homologous secreted trypsin- or chymotrypsin-like serine proteases. KLK2 and KLK3 have the most organ restricted expression profile of all KLKs; specifically, they are abundantly expressed in the luminal epithelium of the prostate. The expression of KLK2 gene is regulated by the androgens and androgen receptor (AR) signaling and like human PSA, serum KLK2 can also function as a biomarker for prostate cancer (PCa). The present work provides biochemical data related to the hydrolytic activities of KLK2 on libraries of fluorescence resonance energy transfer (FRET) peptides in the presence of sodium citrate, a kosmotropic salt that is present in normal prostate tissue and seminal fluid in high concentration. The peptide SYR↓IF (cleaved at↓) was the highly hydrolyzed and best substrate so far reported for KLK2. The sequence YRIF is present in the N-terminal segment (59YRIF62) in the β chain of interleukin-10 receptor. In order to verify the effect of KLK2 in the IL10RB surface expression in the bone marrow-derived macrophages (BMDM) cells, they were incubated with KLK2 at 37ºC for 2 hours. BMDM treated with KLK2 showed a significant reduction in the IL10RB surface expression compared with control group, indicating that KLK2 acts directly on this receptor, decreasing its expression. The effect of this reduction was evaluated trough BMDM activation assay. After incubation of BMDM cells with KLK2, they were washed and incubated with or without LPS, IFN-γ and recombinant IL10. When incubated with recombinant IL10, control macrophage showed a significant reduction of NO, TNF-α and IL-12p40 levels indicating the IL10RB functionality and according to IL10 immunosuppressive effect. However, KLK2 pretreated macrophage maintained NO, TNF-α and IL-12p40 levels, even in the presence of recombinant IL10, leading a proinflammatory status in BMDM culture, while KLK3 doesn't show the same effect. Taken together, the data indicates that KLK2 decreases the surface expression of IL10RB on macrophage cells and contributes to a proinflammatory environment.
Citation Format: Luiz J. Neto, Maria A. Juliano, Juliana R. Oliveira. Substrate specificity of human kallikrein-related peptidase 2 (KLK2) towards beta chain of interleukin-10 receptor [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 3796.
Abstract 3800: Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma cells
Authors: Hamaidia Malik , Hoyos Clotilde , Willems Luc L. 
Published: August 2018

Abstract
Rationale: Clinical evidence indicates that tumor infiltration by tumor associated macrophages (TAMs) correlates with poor prognosis in malignant mesothelioma (MM). By attenuating the immune response, TAMs indeed promote survival of MM cells. TAMs share properties with alternative macrophages (M2) that are activated by anti-inflammatory (e.g. IL-10) or Th2-associated (i.e. IL-4, IL-13) cytokines.
Objectives: We hypothesized that macrophage activation is mediated by a transcriptional program tightly regulated by epigenetic modifications. We focused on the Polycomb Repressive Complex 2 (PRC2) EZH2 lysine methyltransferase responsible for trimethylation of histone H3 at lysine 27 (H3K27me3). We investigated the effect of a selective EZH2 inhibitor (EPZ005687) on tumoricidal activity of primary human monocyte-derived macrophages.
Results: Our data show that inhibition of EZH2 reduces CD206 expression and phagocytic activity of macrophages conditioned in MM pleural effusions (PE-macrophages). Moreover, EZH2 inhibition enhances the cytotoxic potential of PE-macrophages towards MM cells. Inhibition of EZH2 also increases the ability of macrophages to support proliferation of autologous T-cells.
Conclusion: Induction of cytotoxic activity of PE-macrophages via PRC2 EZH2 lysine methyltransferase could be of therapeutic value in MM.
Citation Format: Malik Hamaidia, Clotilde Hoyos, Luc L. Willems. Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma cells [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 3800.
Abstract 3803: Immune escape from NK cells and activated CD8 T cells by miR-183 repression of MICA/B expression in human lung cancer
Authors: Tu Nhan , Trinh Thu Le , Donatelli Sarah S. , Tejera Melba M. , Gilvary Danielle L. , Zhou Jun-Min , Egsioglu Erika A. , Wei Sheng , Coppola Domenico , Djeu Julie Y. 
Published: August 2018

Abstract
Immune escape is a hallmark of cancer. In human lung cancer, we have identified a unique microRNA (miR)-based pathway employed by tumor cells to repress detection by immune cells via the NKG2D-MICA/B receptor-ligand system. MICA/B is readily induced by cell transformation and serves as a danger signal and ligand to alert NK and activated CD8+ T cells. However, immunohistochemical analysis indicated that human lung adenocarcinoma and squamous cell carcinoma specimens express little MICA/B while high levels of miR-183 were detected in both tumor types in a TCGA database. Human lung tumor cell lines confirmed the reverse relationship in expression of MICA/B and miR-183. Importantly, a miR-183 binding site was identified on the 3' untranslated region (UTR) of both MICA and MICB, suggesting its role in MICA/B regulation. Luciferase reporter constructs bearing the 3'UTR of MICA or MICB in 293 cells supported the function of miR-183 in repressing MICA/B expression. Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B. Abundant miR-183 expression in tumor cells was traced to transforming growth factor-beta (TGFβ), as evidenced by anti-sense TGFβ transfection into H1355 or H1299 tumor cells, which subsequently lost miR-183 expression accompanied by MICA/B upregulation. Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8+ T cells that express high levels of NKG2D. Thus, high miR-183 triggered by TGFβ expressed in lung tumor cells can target MICA/B expression to circumvent detection by NKG2D on immune cells.
Citation Format: Nhan Tu, Thu Le Trinh, Sarah S. Donatelli, Melba M. Tejera, Danielle L. Gilvary, Jun-Min Zhou, Erika A. Egsioglu, Sheng Wei, Domenico Coppola, Julie Y. Djeu. Immune escape from NK cells and activated CD8 T cells by miR-183 repression of MICA/B expression in human lung 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 3803.