bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B03: Integrin agonists reduce infiltration of tumor-associated macrophages to promote T-cell mediated anti-tumor immunity
Authors: Khan Samia Q. , Faridi Mohd. H. , Khaliqdina Shehryar J. , Barbosa Antonio J. , Varner Judith A. , Gupta Vineet 
Published: March 2017

Abstract
Tumors associated macrophages (TAMs) mediate neovascularization and promote tumor growth. Integrin CD11b/CD18 is highly expressed on cells of myeloid and granulocytic lineage and mediates their adhesion, migration and tissue recruitment functions. CD11b+ TAMs are present at high numbers in several types of human cancers, including breast and non-small cell lung cancer, and are associated with reduced T-cell mediated anti-tumor immunity. This suggests that reducing infiltration of CD11b+ TAMs could have a therapeutic benefit. Recently, we have developed a novel small molecule CD11b agonist termed leukadherin-1 (LA1) that binds to and allosterically activates integrin CD11b on leukocytes. We also reported that CD11b activation is a more effective strategy for reducing CD11b+ cell tissue infiltration, as compared to integrin antagonists. LA1 binding transiently increases leukocyte adhesion to the vascular endothelium and reduces their transmigration in vivo. Here, we show that LA1 mediated CD11b activation reduced the number of CD11b+ TAMs in two different murine tumor models that was accompanied with diminished primary tumor growth. LA1 treated animals also had significantly reduced tumor angiogenesis and prolonged survival. These improved aspects were accompanied with reduction in vessel density as indicated by reduced intratumoral expression levels of CD31 and αSMA and increased numbers of CD8+ T cells indicating an anti-tumor immune profile response fostering tumor suppression. Our data provide a rationale for using allosteric CD11b agonists to target TAMs as a novel therapeutic approach for treating cancer.
Citation Format: Samia Q. Khan, Mohd. H. Faridi, Shehryar J. Khaliqdina, Antonio J. Barbosa, Judith A. Varner, Vineet Gupta. Integrin agonists reduce infiltration of tumor-associated macrophages to promote T-cell mediated anti-tumor immunity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B03.
Abstract B07: The loss function of BP180 (Collagen type XVII) in skin, leads to a mast cell dependent pro-inflammatory microenvironment which promotes melanoma progression
Authors: Hwang Bin-Jin , Peng Bin , Zhang Yang , Brozowski Jaime Marie , Lin Lin , Williams Scott E. , Li Ning , Liu Zhen , Su Maureen , Thomas Nancy E. , Diaz Luis A. , Liu Zhi 
Published: March 2017

Abstract
BP180, also known as type 17 collagen, is a transmembrane glycoprotein located in the hemidesmosome of epidermal basal keratinocytes. BP180 is a critical cell/matrix adhesion molecule in dermal-epidermal junction of the skin. Various clinical reports indicated that the altered expression of hemidesmosomal protein BP180 is associated with melanoma progression. However, it is unclear whether BP180 is directly involved in melanoma progression. To investigate the role of BP180 in melanoma progression, we generated novel mouse strains lacking BP180 functions in whole body (by crossing floxed mice with germline Cre), in the local skin (tamoxifen-inducible Cre), or in basal keratinocytes (K14-driven Cre). These BP180 functional knockout mice showed dermal-epidermal junction separation in the skin, indicating that the cell/cell matrix adhesion mediated by BP180 is impaired. Loss of BP180 function also lead to a proinflammatory microenvironment in skin accompanied with an influx of immune cells including mast cells, neutrophils and T cells. When tested in B16 mouse melanoma model BP180 functional deficient mice (globally, in the local skin, or in basal keratinocytes) showed significantly increased melanoma progression. These results demonstrated that BP180 deficiency limited in local skin microenvironment or basal keratinocyte is sufficient to promote melanoma progression. To determine whether increased neutrophil or mast cells are required for the accelerated melanoma progression in BP180 functional deficient mice, we injected B16 melanoma cells into mice lacking both mast cells and BP180 function. Mast cell deficiency drastically reduced the inflammation, neutrophil influx into skin and melanoma progression caused by loss of BP180 function. These findings provide the first evidence suggesting that BP180, as a hemidesmosomal cell-cell matrix adhesion protein, plays a vital role in host defense against melanoma progression through modulating basal keratinocytes, neutrophil and mast cells in local tumor microenvironment.
Citation Format: Bin-Jin Hwang, Bin Peng, Yang Zhang, Jaime Marie Brozowski, Lin Lin, Scott E. Williams, Ning Li, Zhen Liu, Maureen Su, Nancy E. Thomas, Luis A. Diaz, Zhi Liu. The loss function of BP180 (Collagen type XVII) in skin, leads to a mast cell dependent pro-inflammatory microenvironment which promotes melanoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B07.
Abstract B12: Independent comparison of the state of the art in-silico HLA typing software
Authors: Ng Alvin , Rozen Steve 
Published: March 2017

Abstract
To accurately characterize the neo-antigen repertoire in tumors, identifying the HLA alleles of the patient is paramount. The binding of the neo-antigens to the patient's specific HLA alleles HLA-restriction has to be determined to identify neo-antigens that might play a role in stimulating an immune response in immunotherapy. The information on the patient's HLA alleles is captured in the next-generation sequencing (NGS) data and has to be accurately teased out using in-silico HLA typing software. However, to our knowledge, until now an independent study of HLA typing software has not been carried out. In this study, five publicly available HLA typing software packages were compared using 106 whole exome sequencing samples from the 1000 Genomes Project and a published dataset of 56 Asian nasopharyngeal tumor-normal pairs with experimentally determined HLA types. Whole exome sequencing samples of varying depth and coverage were chosen to simulate real-world data and test the robustness of the HLA typing software.
Citation Format: Alvin Ng, Steve Rozen. Independent comparison of the state of the art in-silico HLA typing software. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B12.
Abstract B13: Integrative genomic and transcriptomic analysis of 775 human cancer cell lines reveals tumor-derived immune programs and their regulators
Authors: Villani Alexandra-Chloe , Chun Ye , Raychowdhury Raktima , Li Weibo , Eisenhaure Thomas , Regev Aviv , Hacohen Nir 
Published: March 2017

Abstract
The role of tumor cell-derived immune factors in the development of cancer and tumor immunity remains poorly understood. We hypothesized that tumors express recurrent and stable immunoregulatory programs that impact cancer growth and immunity. To identify these programs, we performed an unbiased integrative analysis of chromosomal copy number aberrations and gene expression analysis on 775 primary solid tumor cell lines, derived from 23 different tissues of origin. Using modified versions of GISTIC 2.0 and CONEXIC, a Bayesian module network method, we identified cancer drivers that correlated with specific transcriptional regulatory programs across multiple cell lines (after considering confounding variables, including histology, sub-histology, ethnicity, gender, center of collection, experimental batches and unknown variables using Surrogate Variable Analysis). We identified a total of 60 amplified and 222 deleted somatic regions, of which 52% contained a candidate driver gene whose expression was associated with the expression of a target module. The driver genes consisted of putative novel and known cancer drivers, including deletions in CDKN2A-CDKN2B (q&lt; 4.2E-176), WWOX (q&lt; 5.3E-100), and amplifications in MYC (q&lt; 2.1E-81) and CCND1 (q&lt; 1.4E-44) genes. The target modules were enriched for known cancer-dysregulated processes, including cell cycle (q&lt; 2.1E-91) and DNA damage/repair (q&lt; 9.3E-50), validating the analysis. We identified and focused on immune programs common to several tissues of origin, including a type I interferon-related program (q&lt;9.8E-26), which is likely to impact the tumor immune microenvironment. To validate our predictions, we functionally investigated 8 cell lines with high versus 8 with low expression of the interferon-related immune regulatory program. We validated activation of the pathway at the protein level and found that it was sustained by secreted factors. We found drivers of this program using CRISPR/Cas9 single guide RNAs and small molecule inhibitors, and showed that cancer cells expressing this program modulated activation of co-cultured immune cells. The finding of a stable tumor-derived immune program should help point to new targets for cancer therapy.
Note: This abstract was not presented at the conference.
Citation Format: Alexandra-Chloe Villani, Ye Chun, Raktima Raychowdhury, Weibo Li, Thomas Eisenhaure, Aviv Regev, Nir Hacohen. Integrative genomic and transcriptomic analysis of 775 human cancer cell lines reveals tumor-derived immune programs and their regulators. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B13.
Abstract B42: Role of TRAIL signaling in tumor killing
Authors: Siao Shih-Hong , Hsu Ping-Ning 
Published: March 2017

Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an endogenous ligand, which plays role in immune surveillance and anti-tumor immunity. Binding of TRAIL to its death receptor (DR4 or DR5) leads to receptor oligomerization and recruitment of the death-inducing signaling complex (DISC), activates the caspase-8 and its downstream caspase cascade and ultimately leads to cell death. Although TRAIL induces apoptosis in many tumor cell lines, almost all normal cells are insensitive to TRAIL-induced cell death. The physiological role of TRAIL remains to be elucidated. Recently, scientists have turned their attention to the emerging role of TRAIL in modulating immune responses. TRAIL administration induced anti-inflammatory effects in several autoimmune animal models. All these results suggest an apoptosis-independent role of TRAIL in the immune system. In this study, we studied the role of TRAIL signaling in immune resistance to tumor growth by using the TRAILR-R knockout mice. We demonstrated TRAIL suppressed T cell activation stimulated by anti-CD3/CD28. T cells from TRAIL-R knockout mice resisted to these effects and were with higher proliferation and cytokine production capability to anti-CD3/CD28 stimulation. However, when the melanoma cell lines B16-F10 were inoculated, there was enhanced tumor growth in TRAIL-R knockout mice compared to the wild type control. This finding suggests TRAIL/TRAIL-R interaction may play a role in host against tumor growth. The immunophenotype of the tumor infiltrating lymphocytes and cytokine production are analyzed. Apoptosis and activation of caspases of tumor cells and infiltrating immune cells are also characterized. This study will help to elucidate the role of TRAIL signaling in tumor killing and immune surveillance.
Citation Format: Shih-Hong Siao, Ping-Ning Hsu. Role of TRAIL signaling in tumor killing. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B42.
Abstract B44: Selective stimulation of RIG-I with a novel synthetic RNA induces strong anti-tumor immunity in mouse tumor models
Authors: Barsoum Jim , Renn Marcel , Schuberth Christine , Jakobs Christopher , Schwickart Anna , Schlee Martin , Boorn Jasper van den , Hartmann Gunther 
Published: March 2017

Abstract
We describe a novel immunotherapy approach in which a natural viral defense system is harnessed to stimulate anti-tumor immunity. Cancer immunotherapy has revolutionized oncology in recent years, yet many tumors become resistant or do not respond to current treatments such as checkpoint inhibitors. Stimulation of the innate immune system opens a new therapeutic strategy that could be combined effectively with other immunotherapeutic regimens. The ubiquitously expressed cytosolic RNA receptor retinoic acid inducible gene I (RIG-I) recognizes double-stranded RNA bearing a 5'-triphosphate. RIG-I plays a prominent role in antiviral defense. Its activation induces apoptosis preferentially in tumor cells and simultaneously activates the innate immune system via type I interferon (IFN) signaling. We developed an optimized, fully synthetic oligonucleotide, designated RGT100, which is a RIG-I selective ligand. RGT100 activates the RIG-I pathway leading to the induction of cytokines, including IFN-α and IFN-β. The treatment of tumor-bearing mice with RGT100 induced potent anti-tumor activity against large established B16 melanoma and CT26 colon carcinoma tumors. RGT100 also was efficacious in a spontaneous melanoma model. Histological and flow cytometric analysis of the tumors revealed infiltration and activation of immune cells after RGT100 treatment. RGT100 induced a strong and durable type I IFN response in tumors. Treatment of subcutaneous tumors by intratumor injection led to efficacy of both the treated tumors as well as untreated contralateral tumors. Furthermore, systemic delivery of RGT100 was efficacious against both local subcutaneous B16 melanoma as well as lung metastases. Data support both rapid natural killer (NK) cell-mediated and long-term T cell-mediated anti-tumor activities. Depletion of NK cells blocked the immediate anti-tumor activity of RGT100. In summary, Rigontec's RIG-I-selective ligand RGT100 shows strong anti-tumor activity in several clinically relevant mouse tumor models, while bearing an advantageous safety profile. RGT100 is rapidly progressing toward clinical evaluation in cancer patients. This agent will be evaluated both for single-agent activity as well as in combination with checkpoint inhibitors.
Citation Format: Jim Barsoum, Marcel Renn, Christine Schuberth, Christopher Jakobs, Anna Schwickart, Martin Schlee, Jasper van den Boorn, Gunther Hartmann. Selective stimulation of RIG-I with a novel synthetic RNA induces strong anti-tumor immunity in mouse tumor models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B44.
Abstract B51: Targeting galectin-1 to improve therapeutic efficacy in head and neck cancers
Authors: Nambiar Dhanya K. , Cao Hongbin , Le Quynh Thu 
Published: March 2017

Abstract
Head and neck cancers (HNC) are associated with significant changes in the immune profile, with lower systemic absolute lymphocyte count and reduced tumor-infiltrating lymphocytes (TILs), which are inversely correlated with overall survival. Galectin-1(Gal-1), which is a carbohydrate binding protein, is secreted at high level by cancer cells, including HNC, and contributes to tumor-immune escape and disease progression. Our group has shown that both hypoxia and radiotherapy (RT) can individually stimulate tumor Gal-1 secretion, which is detrimental to therapeutic efficacy. Targeting Gal-1 in HNC therefore may synergize with radiotherapy and/or immunotherapy. Using the CRISPR/Cas9 deletion approach, we developed an orthotopic model of HNC with/without Gal-1 expression. We found that Gal-1 KO tumors showed a marked decrease in tumor growth and nodal metastases. Gal-1 WT tumors had very low infiltration of CD4+/CD8+ T cells (TILs) compared to Gal-1 null tumors. The decrease in TILs was due to both Gal-1-induced apoptosis of activated T cells and Gal-1 inhibition of trans-endothelial T-cell migration, which was confirmed by in vitro assays. Endothelial cells within Gal-1 WT tumors showed uniformed staining of PD-L1 expression by immunohistochemistry, that was not present in Gal-1 null tumors. Similarly, isolated tumor endothelial cells (TECs) from Gal-1 WT tumors showed significantly higher expression of PD-L1 (PD1 ligand) and Gal-9 (Tim-3 ligand) than TECs from Gal-1 null tumor. Concurrently, there were more PD1+ and Tim3+ intra-tumoral T cells within the Gal-1 WT than Gal-1 null tumors. Our study therefore suggest that in addition to T-cell apoptosis, tumor Gal-1 can impede transendothelial T cell migration, leading to less TIL, resulting in immune escape and possible resistance to immune check point therapy. Therefore, a combined approach of targeting Gal-1 with immune checkpoint inhibitors may lead to better therapeutic efficacy in HNC patients.
(Acknowlegement: NIH Grant-R01CA161585-03)
Citation Format: Dhanya K. Nambiar, Hongbin Cao, Quynh Thu Le. Targeting galectin-1 to improve therapeutic efficacy in head and neck cancers. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B51.
Abstract B69: Antitumor effects of combining hemocoagulase with the blocking-microvascular action of microbubbles enhanced ultrasound cavitation on rabbit VX2 liver tumors
Authors: Yang Qian , Tang Peng , Liu Liwen , Ge Shuping , Zhou Xiaodong 
Published: March 2017

Abstract
Substantial effort is being directed toward investigating the use of microbubble enhanced ultrasound cavitation (MEUC) to promote penetrate vascular wall and disrupting circulation in liver tumor. In this study we propose and investigate a new method for combining MEUC with hemocoagulase (HC) atrox, which is effectively a vascular targeting to induce embolism effects and combine these with an antiangiogenic treatment strategy. HC was administered was inserted precisely into the tumor under the guidance of real- time ultrasound with a 21-gauge needle. MEUC were conducted at1 MHz frequency probe (with a 400-cycle pulse length and a pulse repetition frequency of 9 Hz) at peak positive pressure of 1 MPa in combination with the commercial microbubble agent SonoVue. MEUC treatments were performed on 10 min on and off periods and HC was administered for 1KU. Rabbits were implanted VX2 tumor mass to establish a liver tumor model. 7 days after tumor implantation, rabbits presented with single liver tumor were randomly divided into 4 study groups: (1) control group were given injections of saline use micro- pump intravenously. (2) HC only injection. (3) MEUC treatment. (4) MEUC+HC treatment. The MEUC induced an acute reduction of blood flow as confirmed with contrast enhanced ultrasound (CEUS) imaging. QontraXt software quantitative analysis time intensity curve (TIC) of the tumor blood perfusion and microvascular changes. The MEUC+HC treatment group showed significant growth inhibition relative to the MEUC-only (p &lt; 0.01) and HC-only treatment groups (p &lt; 0.01). These results indicate the feasibility of a new approach to combining microbubble enhanced ultrasound cavitation with hemocoagulase.
Citation Format: Qian Yang, Peng Tang, Liwen Liu, Shuping Ge, Xiaodong Zhou. Antitumor effects of combining hemocoagulase with the blocking-microvascular action of microbubbles enhanced ultrasound cavitation on rabbit VX2 liver tumors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B69.
Abstract B80: Natural killer and dendritic cells collaborate in the immune response induced by Cetuximab and IL-15 against triple negative breast cancer
Authors: Juliá Estefanía P. , Pampena María Betina , Rocca Yamila S. , Mordoh José , Levy Estrella M. 
Published: March 2017

Abstract
Background: While the majority of Triple Negative Breast Cancer (TNBC) overexpress epidermal growth factor receptor (EGFR), EGFR inhibition as a monotherapy with Cetuximab is not effective. The study of its mechanism of action is important to find out potentially synergistic combinations. Previously, we demonstrated that Cetuximab can trigger antibody-dependent NK cell-mediated cytotoxicity against TNBC cells. The aim of this study was to investigate the effect of NK cell activation by Cetuximab-coated TNBC cells on Dendritic Cell (DC) function, and the result of its combination with IL-15.
Methods: Human monocyte-derived DCs were co-cultured with autologous isolated NK cells, TNBC cells, Cetuximab and/or IL-15 for 24hs. Costimulatory molecule and activation marker expression in DC and NK cells were analyzed by flow cytometry, and cytokine concentration in culture supernatants was assessed by ELISA. DCs obtained after co-cultures were incubated for 24hs with CD40 ligand transfected fibroblasts to mimic the interaction with CD40L expressing Th cells, and IL-12 was analyzed in culture supernatants by ELISA.
Results: Cetuximab treatment of TNBC cells enhanced DC maturation only when NK cells were present in the co-culture (%CD83+: 6.6±0.7 vs 61.0±17, p&lt;0.001; CD86 MIF: 121±36 vs 1868±833, p&lt;0.01). In concert, NK cells were activated by Cetuximab showing increased CD25 expression and IFN-γ production, a cytokine known to induce DC activation. After subsequent CD40 ligand stimulation, DCs that where co-cultured with Cetuximab activated NK cells had an increased ability to produce IL-12p70. Furthermore, IL-15 combination with Cetuximab not only promoted NK cell cytotoxic activity against TNBC cells, but also induced IFN-γ production and DC maturation.
Conclusions: Our results suggest that besides its anti-proliferative mechanism of action, Cetuximab has immunological effects in an in vitro model of TNBC, promoting NK cell activation and DC maturation, which could be potentiated by the combination with IL-15. This could ultimately result in the priming of T cell-based immunity, which will be evaluated in further studies.
Citation Format: Estefanía P. Juliá, María Betina Pampena, Yamila S. Rocca, José Mordoh, Estrella M. Levy. Natural killer and dendritic cells collaborate in the immune response induced by Cetuximab and IL-15 against triple negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B80.