bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4684: NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
Authors: Brennan Kevin , Gevaert Olivier , Sunwoo John B. , Shin June Ho 
Published: August 2018

Abstract
Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin;} Chromatin modifying enzymes are frequently mutated in cancer, resulting in widespread epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features pronounced DNA hypomethylation. We have identified a similar hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions in NSD1. We identified cancer DNA methylation subtypes by first applying the MethylMix algorithm to whole genome DNA methylation and gene expression data from The Cancer Genome Atlas to identify DNA methylation deregulated genes, followed by consensus clustering to patients based on their profiles of these deregulated genes. The ‘NSD1 subtypes' of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, featuring ectopic expression of developmental transcription factors and genes that are also hypomethylated in Sotos syndrome, a congenital disorder caused by germline NSD1 mutations. Further, the NSD1 subtype of HNSC displays an ‘immune cold' phenotype characterized by low infiltration of tumor-associated leukocytes, particularly pro-inflammatory M1 macrophages and CD8+ T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands. Using an in vivo model, we demonstrate that NSD1 inactivation results in reduced T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. NSD1 inactivation therefore drives widespread oncogene expression across cancer sites, and has implications for immunotherapy. &lt;!–EndFragment–&gt;
Citation Format: Kevin Brennan, Olivier Gevaert, John B. Sunwoo, June Ho Shin. NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma [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 4684.
Abstract 4688: Single-cell discrimination of altered human T cell states in the bladder tumor microenvironment
Authors: Oh David Yoonsuk , Kwek Serena S. , Mangul Serghei , Raju Siddharth S. , Targ Sasha , Burra Arun , Chow Eric , Aran Dvir , Porten Sima , Meng Maxwell V. , Friedlander Terence W. , Ye Chun Jimmie , Fong Lawrence 
Published: August 2018

Abstract
Bladder cancer can be responsive to immunotherapies such as anti-PD-1 and anti-PD-L1 checkpoint inhibitors, but overall response rates are low. Tumor-resident T cells demonstrate considerable heterogeneity as far as antigenic repertoire and phenotype. Whether the bladder tumor environment is enriched for specific types of T cells with a particular functional profile and antigenic specificity, and whether these tumor-specific populations are associated with treatment or response to immunotherapy, remains unclear. We performed single-cell RNA sequencing of CD4+ and CD8+ T cells from localized human bladder tumors and paired adjacent non-malignant bladder. We also assessed resected bladder tumors treated with neoadjuvant chemotherapy or atezolizumab (anti-PD-L1) as part of an ongoing phase II trial. We find both known and unexpected CD4+ T cell functional populations that are specific to the tumor microenvironment, including regulatory T cells and a novel population of cytotoxic CD4+ T cells. Furthermore, by combining whole-transcriptome data with paired T cell receptor identification on single cells, we find that tumor-specific CD4+ populations are clonally expanded and utilize an antigenic repertoire which is distinct from uninvolved bladder. These findings provide evidence for specialization of both phenotype and antigenic specificity of CD4+ T cells in the bladder tumor environment, and indicate that a limited number of tumor-specific antigens may drive in situ expansion and differentiation of specialized CD4+ subsets whose function may be critical to tumor control.
Citation Format: David Yoonsuk Oh, Serena S. Kwek, Serghei Mangul, Siddharth S. Raju, Sasha Targ, Arun Burra, Eric Chow, Dvir Aran, Sima Porten, Maxwell V. Meng, Terence W. Friedlander, Chun Jimmie Ye, Lawrence Fong. Single-cell discrimination of altered human T cell states in the bladder tumor microenvironment [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 4688.
Abstract 4690: FoxP3+T cells program/re-program the prostatic tumor microenvironment
Authors: Kumar Sanjay , III James Stoke , Malik Shalie , Singh Udai P. , Ponnazhagan Selvarangan , Manne Upender , Mishra Manoj K. 
Published: August 2018

Abstract
Foxp3+ T cells play a critical role in maintaining immunological tolerance by regulating functions of other immune cells, thus preventing autoimmunity. Previous studies have demonstrated the importance of Foxp3+ T cells in the tumor, however, the role increasingly recruited FoxP3+ T cells in the programming of prostatic tumor microenvironment is not well illustrated. Therefore, in this study, we have investigated the role of Foxp3+ T cells in the prostatic tumor microenvironment with the notion that increased Foxp3+ T cells facilitate tumor growth. To accomplish this, we carried out tumor induction studies in C57/BL-6 mice using transgenic adenocarcinoma of mouse prostate (TRAMP cell lines: -C1, -C2 and -C3) as tumor models. Mice were administered with TRAMP (C1-3) cells using the Matrigel system. TRAMP-C3 cells are non-tumorigenic while TRAMP-C1 and TRAMP-C2 cells form tumors. Mice were sacrificed by cervical dislocation when tumor sizes reached ~18-20mm in diameter. To prepare single cell suspension, spleen and tumor were dissected out and cells were stained with various cell surface as well as intracellular immune markers to determine the number of Foxp3+ T cells and other immune cells in the prostatic tumor microenvironment. Our findings suggest that the high number of Foxp3+ T cells was found in the spleen and tumor of TRAMP-C1 and TRAMP-C2 mice than the spleen and tiny tumor of TRAMP-C3 mice. Furthermore, the number of cytotoxic T lymphocytes and NK cells were also observed to be low in the tumorigenic TRAMP-C1 and -C2 mice as compared to non-tumorigenic mice (TRAMP-C3). Therefore, our findings suggest that the number of Foxp3+ T cells may play a critical role in shaping the prostatic tumor microenvironment.
Citation Format: Sanjay Kumar, James Stoke III, Shalie Malik, Udai P. Singh, Selvarangan Ponnazhagan, Upender Manne, Manoj K. Mishra. FoxP3+T cells program/re-program the prostatic tumor microenvironment [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 4690.
Abstract 4699: Identification of novel potential biomarkers of response to sunitinib in glioblastoma
Authors: Noman Abu Shadat Mohammod , Abdulkarim Bassam , Sabri Siham 
Published: August 2018

Abstract
Introduction: Glioblastoma multiforme (GBM) is the most advanced and aggressive form of primary malignant brain tumors in adults. O6-Methylguanine methyltransferase (MGMT) is a DNA repair protein well known for its role in resistance to temozolomide used in standard treatment of patients newly diagnosed with GBM. Sunitinib is an oral multitargeting receptor tyrosine kinase (RTK) inhibitor with antiangiogenic and antiproliferative activities targeting several RTKs. Our group has previously shown the role of MGMT as a negative regulator of angiogenesis and invasion and the differential antiproliferative effect of sunitinib based on expression of MGMT in GBM. Recent gene expression profiling (GEP) studies showed that besides its effects on RTKs, sunitinib affects the expression level of other genes at the transcriptional level in different cancer types. We hypothesized that: (i) the mechanism of action of sunitinib may not be limited to direct inhibition of its known targets (RTKs) in GBM and (ii) expression of MGMT may affect response of GBM tumor cells to sunitinib. We performed GEP analysis to identify genes that could be potentially modulated in response to sunitinib in GBM cell lines isogenic for MGMT. Empty vector (EV)-transfected T98/EV cells with constitutive expression of MGMT and its knockdown counterpart T98/MGMT-shRNA were treated with sunitinib or vehicle control. Treatment of T98/EV and T98/MGMT-shRNA cell lines with sunitinib significantly changed the expression of over 2,000 gene transcripts (analysis performed at Genome Quebec Innovation center, McGill University). Lists of significant genes were fitted into previously known biochemical pathways, available among the canonical pathways from various databases provided by ConsensusPathDB (CPDB). Strikingly, immune system was among the top significantly enriched pathways (p-value&lt;10-3), with some immune pathways not previously reported for response to sunitinib.
Conclusion: Our study opens new avenues to further understand the mechanisms of action of sunitinib, investigate its immunomodulatory effects, and identify biomarkers for selection of patients who might benefit from the combination of antiangiogenic and immunebased strategies in GBM.
Funding Acknowledgment: Cancer Research Society Operating Grant Competition #22716, and Higher Education Quality Enhancement Project (HEQEP)- Window -4 (Grant Id. CP-4023), University Grant Commission (UGC), Bangladesh.
Citation Format: Abu Shadat Mohammod Noman, Bassam Abdulkarim, Siham Sabri. Identification of novel potential biomarkers of response to sunitinib in glioblastoma [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 4699.
Abstract 47: Brain metastatic versus non-metastatic breast cancer exosomes influence astrocyte response
Authors: Sayyad Megan , Puchalapalli Madhavi , Hu Bin , Koblinski Jennifer 
Published: August 2018

Abstract
Brain metastasis is a devastating, late-stage event affecting 10-30% of breast cancer patients, but it is unclear how breast cancer cells can cross the blood-brain barrier (BBB) and colonize the unique brain environment. Exosomes, endosomal-derived extracellular vesicles, have been reported to support premetastatic niche formation through recruitment of tumor growth-supporting cells, creating sites conducive to cancer development. Still, it is not known how exosomes might prime the distinctive brain environment for metastasis despite the ability of circulating exosomes to readily cross the BBB. Glial cells, namely astrocytes and microglia, are important contributors to brain metastasis, and astrocytes in particular secrete exosomes that promote tumor outgrowth in the brain. We therefore investigated the effects of breast cancer exosomes on astrocytes in promoting brain premetastatic niche formation. Using ultracentrifugation, we isolated exosomes from 4T1 metastatic and 67NR nonmetastatic mouse mammary carcinoma and MDA-MB-231 human triple-negative breast cancer cell-conditioned media. Exosomes were characterized using Western immunoblot, dynamic light scatter analysis, and transmission electron microscopy, and labeled with a fluorescent lipid dye. Mouse and human astrocytes were then treated with either 4T1 or MDA-MB-231 exosomes, respectively, and vesicle internalization was assessed using confocal microscopy. Astrocytes were indeed found to internalize cancer exosomes in vitro. Using qPCR analysis, we explored gene expression changes in mouse astrocytes treated with 4T1 exosomes compared to those treated with 67NR exosome nonmetastatic controls. 4T1 exosomes were found to significantly upregulate expression of tenascin C, an astrocyte-derived brain extracellular matrix protein, suggesting the brain matrix could be remodeled prior to cancer cell arrival. Further, astrocytes treated with 4T1 exosomes exhibited significant upregulation of inflammation-associated genes, namely COX-2, IL-6, CCL4 and PDGF-alpha, genes also associated with cancer and metastasis, specifically to the brain. Alternatively, 67NR exosome treated-astrocytes exhibited significant downregulation in these genes of interest, suggesting that there is a unique response profile associated with nonmetastatic versus metastatic breast cancer-derived exosomes. Taken together, these findings suggest that breast cancer exosomes could drive transformation of the brain environment towards a prometastatic site.
Citation Format: Megan Sayyad, Madhavi Puchalapalli, Bin Hu, Jennifer Koblinski. Brain metastatic versus non-metastatic breast cancer exosomes influence astrocyte response [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 47.
Abstract 4703: The inhibitor of apoptosis protein (IAP) antagonist Debio 1143 enhances the immune response to anti-PD1/L1 inhibitors in vitro and in vivo
Authors: Attinger Antoine , Gavillet Bruno , Chessex Anne Vaslin , Wiedemann Norbert , Vuagniaux Gregoire 
Published: August 2018

Abstract
Background: Debio 1143 is an oral antagonist of IAPs, currently in clinical development, which sensitizes tumor cells to radiation- or chemotherapy-induced apoptosis. IAPs inhibitors modulate NF-κB signaling and drive the expression of genes relevant for inflammation and immunity. Here, we hypothesized that Debio 1143 could improve antitumor immunity by directly enhancing T-lymphocyte activation and by improving the effects of immune checkpoint inhibitors in vitro and in vivo.
Methods: Ex vivo human PBMC anti-CD3/CD28 stimulation and modified mixed-lymphocyte reaction assays were performed to evaluate the immunostimulatory potential of Debio 1143 alone or in combination with the anti-PD-1 antibody nivolumab (N= 5 donors). T cells' proliferation and activation were measured by flow cytometry and cytokine release was measured by ELISA. The antitumor activity of an anti-PD-L1 antibody (5 mg/kg BIW IP) was tested either alone or in combination with Debio 1143 (100 mg/kg QD1-5 PO) in MBT-2 immunocompetent mouse model of bladder cancer over 3 weeks (n=8 /group).
Results: Debio 1143 significantly enhanced CD4+ and CD8+ intracellular IFNγ expression in a concentration-dependent manner following anti-CD3/CD28 stimulation. This result was confirmed using a mixed-lymphocyte reaction assay, where Debio 1143 at concentrations achieved in clinical studies significantly increased IFNγ expression by activated CD4+ cells, and this effect was even further increased in presence of nivolumab. In MBT-2 tumor-bearing mice, the combination of Debio 1143 and anti-PD-L1 antibody significantly decreased tumor growth (P=0.001 using two-sided t-test) and increased survival, whereas monotherapies only displayed moderate activities (median survival time of 42 days vs. 33 or 28 days for Debio 1143 or anti-PD-L1 alone, respectively).
Conclusion: These data show a key mechanistic role for future combination therapy of the IAP antagonist Debio 1143 and immune-checkpoint agents in cancer patients. This synergy will be further explored in a phase-Ib dose-finding clinical study combining Debio 1143 and Avelumab (anti-PD-L1) in patients with advanced solid malignancies and non-small cell lung cancer (CT# 03270176).
Citation Format: Antoine Attinger, Bruno Gavillet, Anne Vaslin Chessex, Norbert Wiedemann, Gregoire Vuagniaux. The inhibitor of apoptosis protein (IAP) antagonist Debio 1143 enhances the immune response to anti-PD1/L1 inhibitors in vitro and in vivo [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 4703.
Abstract 4711: Modulation of NFκ-B signaling to optimize antitumor characteristics in macrophages
Authors: Liu Esther , Hoover Alyssa A. , Harris Whitney R. , Barham Whitney , Tikhomirov Oleg , Khabele Dineo , Mirafzahli Zahra , Giorgio Todd D. , Wilson Andrew J. , Yull Fiona E. 
Published: August 2018

Abstract
While it is known that nuclear factor κ-B (NF-κB) signaling within macrophages regulates expression of downstream targets that can mediate either pro- or antitumor functions, the mechanisms that define predominant characteristics are not well understood. As macrophages are present in the tumor microenvironment of diverse tumor types, their characteristics have the potential to either support or hinder tumor growth and metastatic spread. Therefore, a method to shift the balance of tumor associated macrophages from pro- to antitumor functions could potentially target tumor cells directly and also recruit and activate other immune cells, resulting in significant therapeutic benefit. Our studies are designed to gain an understanding of how to use modulation of NF-κB signaling as the “pinch point” to generate antitumor phenotypes and determine how to achieve this modulation in a patient. We are using immortalized bone marrow-derived macrophages or ex vivo tumor-associated macrophages in cell culture approaches and inducible transgenic mice in in vivo approaches to investigate the mechanisms by which NF-κB defines macrophage characteristics. Interactions with tumor cells are also being investigated using co-culture and murine models. Our data suggests that high levels of NFκ-B activity in macrophages induce both direct tumor cell killing and immune stimulating responses. We are testing two different translational approaches. The first is liposomal muramyl tripeptide ethanolamine that acts as an immune stimulant by increasing NF-κB activity in macrophages. The second is preferential delivery of siRNA against the inhibitor of NFκ-B (IκB-alpha) to tumor-associated macrophages using polymeric nanoparticles. We hope to better understand the mechanisms by which NFκ-B regulates macrophage functions to inform development of a novel macrophage-based immunotherapy that could be effective across a wide spectrum of solid tumors and metastatic disease.
Citation Format: Esther Liu, Alyssa A. Hoover, Whitney R. Harris, Whitney Barham, Oleg Tikhomirov, Dineo Khabele, Zahra Mirafzahli, Todd D. Giorgio, Andrew J. Wilson, Fiona E. Yull. Modulation of NFκ-B signaling to optimize antitumor characteristics in macrophages [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 4711.
Abstract 4715: Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that progressed despite chemotherapy and check-point inhibitors
Authors: Check Jerome H. , Check Diane , Poretta Trina 
Published: August 2018

Abstract
The US FDA approved an investigator initiated phase II 40 patient study to treat patients with stage IIIB or IV non-small cell lung cancer who have progressed despite a minimum of 2 rounds of chemo or immunotherapy with the progesterone receptor modulator mifepristone taken orally at 300mg/day (www.clinicaltrials.gov). The first patient in the study reported at the 2017 AACR meeting with stage IV lung cancer with brain metastasis has had non-progressive disease with excellent quality of life (ECOG-zero) after 24 months on mifepristone therapy. His lung cancer was PD-L1 negative, and thus he did not receive check-point inhibitors. We report, herein, the clinical outcome of the second patient with stage IV disease who not only progressed despite 3 chemotherapy regimens but also nivolumab (she was positive for the PD-L1 marker). The second patient in the study began 300mg/day oral mifepristone at age 68. Her stage IV lung cancer had progressed despite 4 cycles of carboplatin, permetrexed, and bevacizumab, 6 cycles of carboplatin and docetaxel, and 6 cycles of erlotinib. Finally she progressed and treatment was stopped after 11 cycles of nivolumab (PD-L1 marker present). After 1 year of oral mifepristone there have been no new metastatic lesions. She is ECOG 1 (related to chronic obstructive lung disease). Her cancer is stable with slight reduction in some metastatic lesions. More importantly she states she feels better than at any time since her initial diagnosis. The mechanism of action of mifepristone is hypothesized to be related to suppressing a key immunosuppressive protein that seems to be required for rapidly growing cells (e.g., possibly cancer stem cells), to proliferate known as the progesterone induced blocking factor (PIBF). This protein stablizes perforin granules in natural killer cells, thus obviating their mechanism for cytotoxicity. Mifepristone has been shown to suppress the intracytoplasmic immunosuppressive isoform in cancer cell line studies. Mifepristone can also diminish T-cell cytotoxicity. Progesterone receptor modulators may provide a new treatment option for advanced non-small cell lung cancer, even those positive for the PD-L1 marker that progresses despite treatment with chemotherapy and check-point inhibitors. Because intracytoplasmic PIBF is present in only mesenchymal, embryonic, trophoblast, or cancer cells suppressing this protein does not engender any health risks - oral mifepristone is well tolerated.
Citation Format: Jerome H. Check, Diane Check, Trina Poretta. Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that progressed despite chemotherapy and check-point inhibitors [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 4715.