bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A071: Identification and characterization of long intergenic non-coding RNAs (lincRNAs) governing T cell development and function
Authors: Bailis Will , Harman Christian , Henao-Mejia Jorge , Williams Adam , Goff Loyall , Rinn John , Flavell Richard 
Published: November 2016

Abstract
Although a large portion of the human genome is actively transcribed, only a fraction of these RNAs are protein-coding genes. It is now well appreciated that these non-coding transcripts are not only highly diverse in size and structure, but are functional and can exert effects on a vast number of cellular processes. Long intergenic non-coding RNAs (lincRNA) have recently been shown to be key regulators of gene expression during development and oncogenesis. While the growth factors, signaling pathways, and microRNAs that govern lymphoid development and function have been extensively studied, the contribution of these long non-coding RNAs remains poorly characterized. To address this, we performed a genome-wide analysis of lincRNA expression throughout lymphoid and T-lineage development. Bone marrow lymphoid primed multipotent progenitors, DN1-4 and DP thymocytes, as well as mature naïve CD4+ T cells and differentiated helper T cells were sorted and subjected to RNAseq analysis; multiple unique lincRNAs were identified at each stage of development. Transgenic knockout mice were then generated for candidate lincRNAs and analyzed to characterize their function. Through this approach we have identified lincRNAs that regulate both early T lineage and lymphoid commitment as well as mature T cell differentiation and function. These findings offer novel insight into the regulation of lymphoid development and function and expand our understanding of the role non-coding transcripts play in hematopoiesis.
Citation Format: Will Bailis, Christian Harman, Jorge Henao-Mejia, Adam Williams, Loyall Goff, John Rinn, Richard Flavell. Identification and characterization of long intergenic non-coding RNAs (lincRNAs) governing T cell development and function [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A071.
Abstract A081: Chemical biology of microbial metabolite targets in host immunity
Authors: Wang Yen-Chih 
Published: November 2016

Abstract
Microbiota generates unique metabolites to modulate host immunity associated with pathogen resistance and inflammatory diseases, but the specific factors and mechanisms of actions are not well understood. To the end, the Hang and Mucida laboratories have recently identified a secreted peptidoglycan hydrolase, SagA, from E. faecium that generates uniquely active muropeptides that enhance host epithelial barrier integrity and resistance to enteric pathogens in worms and mice. The molecular targets of SagA-generated muropeptides are still unknown and will be addressed using chemical biology and proteomics approaches. Here, we report progress towards the synthesis of SagA-generated muropeptide chemical probes for target identification of specific protein receptors and signaling pathways. Elucidation of SagA-muropeptide protein targets should reveal new pathways to modulate host immunity and inflammation-associated diseases and cancer.
Citation Format: Yen-Chih Wang. Chemical biology of microbial metabolite targets in host immunity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A081.
Abstract A083: Molecular profiling of CD8 T cells from autochthonous melanoma identifies Maf as driver of T cell exhaustion
Authors: Verdeil Gregory , Giordano Marilyn , Schmitt-Verhulst Anne-Marie , Speiser Daniel , Imbratta Claire 
Published: November 2016

Abstract
T-cells infiltrating neoplasms express surface molecules typical of chronically virus-stimulated T-cells, often termed “exhausted” T-cells. We analyzed the transcriptome of “exhausted” CD8 T-cells infiltrating autochthonous melanomas compared to those of naïve and acutely stimulated CD8 T-cells. In spite of strong similarities between transcriptional signatures of tumor- and virally-induced exhausted CD8 T-cells, notable differences appeared. Among transcriptional regulators, Nr4a2 was expressed in both exhaustions, whereas Maf was highly over-expressed only in tumor-exhausted T-cells. Anti-tumor CD8 T-cells transduced to express Maf showed dampened anti-tumor activity upon adoptive transfer, whereas Nr2a4 over-expression was without effect. Maf-expressing CD8 T-cells showed unaltered homeostasis but failed to accumulate in tumor-bearing hosts and developed defective anti-tumor secondary responses. We also found that Maf expression in CD8 T cells induced part of the transcriptional program associated with tumor-induced exhaustion. We further identified TGFβ and IL-6 as main inducers of Maf expression in CD8 T-cells and showed that Maf-deleted tumor specific CD8 T-cells were much more potent to restrain tumor growth in vivo. Therefore the melanoma microenvironment contributes to skewing of CD8 T-cell differentiation programs, in part by TGFβ/IL-6 mediated induction of Maf.
Citation Format: Gregory Verdeil, Marilyn Giordano, Anne-Marie Schmitt-Verhulst, Daniel Speiser, Claire Imbratta. Molecular profiling of CD8 T cells from autochthonous melanoma identifies Maf as driver of T cell exhaustion [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A083.
Abstract A098: A role for fibrosis in promoting pro-tumor immune response in breast cancer
Authors: Maller Ori , Cassereau Luke , Drain Allison , Ruffell Brian , Acerbi Irene , Broz Miranda , Munson Jennifer , Swartz Melody , Krummel Matthew , Coussens Lisa , Weaver Valerie 
Published: November 2016

Abstract
We established a positive correlation between a fibrotic phenotype in human breast tumors — especially the Her2 and basal-like breast cancer subtypes — and CD45 and CD68 positive immune cell infiltration. We were interested in elucidating how this fibrotic phenotype may influence the immune response. To address this question, we examined if matrix stiffness alters the function of STAT3, a central regulator of tumor inflammation. We hypothesize that tissue fibrosis promotes STAT3 signaling in mammary tumor cells and alter the cytokine milieu to induce a pro-tumor immune response. We found that ECM stiffness directly enhanced STAT3 phosphorylation in tumor cells both in vitro and in vivo. Our data suggest the fibrotic phenotype promotes STAT3 activity, enhancement of which may drive a pro-tumor immune response. Indeed, we observed several alterations in cytokines and immune cell populations upon STAT3 ablation consistent with anti-tumor immune response. Interestingly, our data also suggest STAT3 knockout in tumor cells doesn't necessary influence immune cell infiltration, but rather their differentiation in mammary tumors. Finally, we investigated if matrix stiffness has potentiated macrophage differentiation when cultured with specific immunosuppressive cytokines. Overall, our work reveals a novel mechanistic insight into how a pro-tumor immune response stems from the interplay between fibrosis and STAT3 signaling in tumor cells. As such, our findings may stimulate an interest in exploring combinational treatment options with anti-fibrotic agents and immunotherapy.
Citation Format: Ori Maller, Luke Cassereau, Allison Drain, Brian Ruffell, Irene Acerbi, Miranda Broz, Jennifer Munson, Melody Swartz, Matthew Krummel, Lisa Coussens, Valerie Weaver. A role for fibrosis in promoting pro-tumor immune response in breast cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A098.
Abstract A110: Detailed resolution analysis reveals spatial heterogeneity of T cell distribution in the invasive margin of colorectal cancer liver metastases
Authors: Berthel Anna , Zoernig Inka , Suarez-Carmona Meggy , Kahlert Christoph , Klupp Fee , Ulrich Alexis , Weitz Juergen , Jaeger Dirk , Niels Halama 
Published: November 2016

Abstract
On a broader scale T cell density and localization in colorectal cancer liver metastases (CRC-LM) have prognostic and predictive implications, while T cell distribution at higher resolutions has not been fully investigated. As the invasive front of CRC-LM represents a clear border between malignant tissue and adjacent normal liver tissue, a detailed resolution analysis of T cell distribution in this region could be performed. Tissue areas of 1 square millimeter size from different patients were analyzed by high-throughput whole slide imaging technology, showing distinct density patterns of T cell localization in relation to the malignant tissue across the invasive margins. Unsupervised clustering revealed specific groups of patients with T cell aggregates limited to a given distance from the tumor. Furthermore, regions with T cells in close contact to the tumor usually had elevated T cell numbers further away from the tumor, whereas the intermediate area showed limited enrichment. There seems to be a distance of around 10 to 30 micrometer from the tumor where a decrease in T cells is common. Interestingly, 68 percent of distant T cells were identified to be in close contact with tumor-associated macrophages. Therefore, the spatial heterogeneity of T cell distribution in the invasive margin could be accounted for interactions with immunosuppressive cells, cell-matrix interactions or chemotactic fields potentially generated by tumor or endothelial cells, which is currently investigated. Whether the presence of the observed patterns has clinical importance and might change under therapy remains to be seen. In summary, this high resolution analysis of T cell distribution within the invasive front of CRC-LM reveals insights into the detailed localization of T cells and possible spatial immunosuppressive hurdles that need to be overcome by immunotherapies. The analysis of reversal of these spatial profiles could serve as a biomarker for successful therapies.
Citation Format: Anna Berthel, Inka Zoernig, Meggy Suarez-Carmona, Christoph Kahlert, Fee Klupp, Alexis Ulrich, Juergen Weitz, Dirk Jaeger, Halama Niels. Detailed resolution analysis reveals spatial heterogeneity of T cell distribution in the invasive margin of colorectal cancer liver metastases [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A110.
Abstract A131: B7-H1 identifies tumor-reactive effector CD8 T cells susceptible of deletion by agonist PD-L1 antibodies
Authors: Cao Siyu , Liu Xin , Wu Xiaosheng , Mansfield Aaron , Dong Haidong 
Published: November 2016

Abstract
B7-H1 (aka PD-L1) blocking antibodies have been tested in the treatment of human cancers through blocking B7-H1 expressed by tumor cells; however, its impact on B7-H1 expressed by tumor-reactive CD8+ T cells is still unknown. Here, we report that tumor-reactive CD8+ T cells expressing B7-H1 were functional effector cells. An agonist antibody to PD-L1 deleted B7-H1+ PD-1+ tumor-reactive CD8+ T cells via activation of p38 MAPK, and failed to suppress tumor growth. As activation of p38 MAPK leads to CD8+ T cell apoptosis upon T cell activation, a PD-L1 antibody that activated p38 MAPK enhanced apoptosis of activated CD8+ T cells. An intracellular molecule, DNA-PKcs, was identified in association with B7-H1 and a DNA-PKcs inhibitor increased p38 MAPK activation in wild type but not in B7-H1 deficient CD8+ T cells. Our results suggest B7-H1 suppresses p38 MAPK activation via DNA-PKcs to prevent CD8+ T cell death. To maximize antitumor function, PD-L1 antibodies should be selected to avoid their collateral activation of p38 MAPK in tumor-reactive CD8+ T cells.
Citation Format: Siyu Cao, Xin Liu, Xiaosheng Wu, Aaron Mansfield, Haidong Dong. B7-H1 identifies tumor-reactive effector CD8 T cells susceptible of deletion by agonist PD-L1 antibodies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A131.
Abstract A135: Novel immunotherapy for intractable pancreatic cancer focusing on the myeloid derived suppressor cells in the tumor microenvironment
Authors: Tsuchikawa Takahiro , Takeuchi Shintaro , Nakamura Toru , Takahashi Mizuna , Inoko kazuho , Kushibiki Toshihiro , Hontani Koji , Ono Masato , Kuwabara Shota , Shichinohe Toshiaki , Hirano Satoshi 
Published: November 2016

Abstract
Pancreatic cancer is one of malignant diseases with poor prognosis. Despite the recent progress for preoperative neoadjuvant chemoradiotherapy, the long term prognosis is still poor to make forward new treatment strategy. We have recently reported novel mechanism of anticancer reagents to impact patients' prognosis improving tumor microenvironment other than its direct cytotoxic effects (Ann Surg Oncol 2013, Cancer Sci 2014). The underlying mechanism include inhibition of HLA class I down regulation and Treg infiltration, increase of CD4 and CD8 T cell infiltration (Int J Clin Oncol 2015, Cancer Res 2015). Here we report that GM-CSF production was significantly enhanced in various PDAC cell lines after treatment with chemotherapy including gemcitabine or 5-FU, which induced the differentiation of CD14 positive monocytes into myeloid-derived suppressor cells (MDSC). This differentiation was promoted through MAPK signal pathway or NFkB pathway. Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when co-cultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in 68 PDAC patients analyzed by immunohistochemistry. We expect that postoperative prognosis of pancreatic cancer would be more improved by multidisciplinary strategy targeting MDSC and GM-CSF followed by curative surgical intervention.
Citation Format: Takahiro Tsuchikawa, Shintaro Takeuchi, Toru Nakamura, Mizuna Takahashi, kazuho Inoko, Toshihiro Kushibiki, Koji Hontani, Masato Ono, Shota Kuwabara, Toshiaki Shichinohe, Satoshi Hirano. Novel immunotherapy for intractable pancreatic cancer focusing on the myeloid derived suppressor cells in the tumor microenvironment [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A135.
Abstract B024: First-in-class antibody targeting soluble NKG2D ligand sMIC to enhance checkpoint cancer immunotherapy
Authors: Wu Jennifer D. , Zhang Jinyu , Basher Fahmin , Rubinstein Mark 
Published: November 2016

Abstract
In response to oncogenic insult, human cells were induced to express a family of MHC I-chain related molecules A and B (MICA and MICB, generally termed MIC) on the surface which serve as the ligands for the activating immune receptor NKG2D expressed by all human NK, CD8 T, NKT, and subsets of γδ T cells. Theoretically, engagement of NKG2D by tumor cell surface MIC is deemed to signal and provoke the immune system to eliminate transformed cells. Clinically, almost all advanced tumors in cancer patients produce soluble MIC through proteolytic shedding mediated by metalloproteases, or by release in exosomes derived from the cell membrane. Tumor-derived sMIC is known to be highly immune suppressive and profoundly insults the immune system by downregulating receptor NKG2D expression on effector NK and T cells, driving the expansion of tumor-favoring myeloid suppression cells, skewing macrophages into alternatively activated phenotypes, and perturbing NK cell peripheral maintenance. High levels of serum sMIC significantly correlate with advanced diseases of many types of cancer. These observations clearly endorse sMIC to be a cancer immune therapeutic target. However, due to mice lack homologues to human MIC, this concept was not proven until our recent studies. Using a “humanized” MIC-transgenic spontaneous mouse model which recapitulates the NKG2D-mediated onco-immune dynamics of human cancer patients, we show that neutralizing circulating sMIC with a first-in-field non-blocking antibody B10 that does not block the interaction of MIC with NKG2D revamps endogenous innate and antigen-specific CD8 T cell responses and remodels tumor microenvironment to be more immune reactive. We show that therapy with the non-blocking sMIC-neutralizing antibody results in effectively debulk of primary tumor and elimination of metastasis, with no observed toxicity. Furthermore, we show that clearing sMIC with the first-in-class neutralizing antibody B10 also enhanced the efficacy of other cancer immunotherapeutic modalities, such as immune checkpoint blockade or adoptive cell-based therapy pre-clinically. Our study has launched a new avenue of cancer immunotherapy which can be readily translated into clinical trials.
Citation Format: Jennifer D. Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein. First-in-class antibody targeting soluble NKG2D ligand sMIC to enhance checkpoint cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B024.
Abstract B026: MDSCs and CD8 effector memory T cells correlate with survival in melanoma patients treated with ipilimumab
Authors: Coaña Yago Pico De , Wolodarski Maria , Poschke Isabel , Yoshimoto Yuya , Masucci Giuseppe , Hansson Johan , Kiessling Rolf 
Published: November 2016

Abstract
Purpose: To monitor the immune system of ipilimumab treated patients in order to investigate potential mechanisms of action that may correlate with treatment outcome.
Experimental Design: 103 blood samples from 43 patients with advanced melanoma were taken before, during and at the end of treatment. Hematological parameters were measured and multicolor flow cytometry analysis was performed in fresh samples within two hours of sample collection. Endpoints were clinical benefit and overall survival (OS).
Results: Strong differences in immune parameters such as CD25, CCR7 and CD15 in fresh and cryopreserved samples were observed. Treatment increased absolute lymphocyte counts, eosinophils and CD3+CD4+ICOS+ cells. Changes in CD4 memory populations were additionally observed, resulting in a frequency shift towards effector and central memory cells. Ipilimumab decreased frequencies of Tregs, polymorphonuclear MDSCs and production of suppressive mediators iNOS and arginase-1 by myeloid cells. Low monocytic MDSC frequencies after the first infusion were correlated with OS. At the end of treatment, an increase in CD8 effector memory T cells was correlated with clinical benefit and OS.
Conclusions: Analyzing immune parameters in fresh samples allows for accurate measurements of cell populations that are affected by cryopreservation. Ipilimumab treatment resulted in an overall activation of the immune system along with a diminished suppressive state. Patients who additionally had a decrease in monocytic MDSCs or an increase in CD8 effector memory T cells presented increased OS and clinical benefit. Measuring these parameters during ipilimumab treatment could provide insights on clinical responses and suggest modifications to the therapeutic approach.
Citation Format: Yago Pico De Coaña, Maria Wolodarski, Isabel Poschke, Yuya Yoshimoto, Giuseppe Masucci, Johan Hansson, Rolf Kiessling. MDSCs and CD8 effector memory T cells correlate with survival in melanoma patients treated with ipilimumab [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B026.
Abstract B048: A novel PI3K delta inhibitor suppresses tumor progression by immune modulation
Authors: Xu ZuSheng , Lou Yangtong , Tan Jie , Wang Chong , Ge Xiaomei , Gu Ying , Zhou He 
Published: November 2016

Abstract
Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors have shown anti-tumor efficacy in leukemia in the clinic and one such compound, idelalisib, was approved by the FDA for the treatment of relapsed chronic lymphocytic leukemia (CLL) in 2014. A novel PI3Kδ inhibitor, YY-20394, was developed with specific selectivity against PI3Kδ and inhibited PI3Kδ expressing human tumor cells growth both in vitro and in vivo. YY-20394 was then tested in orthotopic murine breast carcinoma 4T1 model in BALB/c mice. Despite mild killing against 4T1 tumor cells in vitro with an IC50 of around 28 μM, YY-20394 significantly inhibited 4T1 primary tumor growth as well as lung metastasis with dose dependency. It also extended the overall survival of 4T1 tumor bearing animals both in resection and non-resection settings. The inhibition of primary tumor growth and metastasis were attenuated in BALB/c nude mice, indicating T cells played an important role in YY-20394's anti-tumor/anti-metastasis efficacy. YY-20394 displayed significant anti-tumor efficacy in other syngeneic mouse tumor models tested including mouse colorectal cancer models MC-38 model in C57BL/c mice and CT26 model in BALB/c mice. More importantly, YY-20394 synergistically enhanced the anti-tumor efficacy of anti-PD-L1 antibody in CT26 model with 100% of the animals survived during a 60 day experimental period. YY-20394 is well tolerated by the animals with no treatment-related toxicity observed in these efficacy studies. These data suggest the YY-20394, a novel PI3Kδ inhibitor, represents a promising and safe immune modulator and shows great potential in combining with immune check point inhibitors in cancer therapies.
Citation Format: ZuSheng Xu, Yangtong Lou, Jie Tan, Chong Wang, Xiaomei Ge, Ying Gu, He Zhou. A novel PI3K delta inhibitor suppresses tumor progression by immune modulation [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B048.