bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A02: Gut microbiome controls growth of liver tumors
Authors: Ma Chi , Han Miaojun , Heinrich Bernd , Fu Qiong , Zhang Qianfei , Wang Xin W. , Trinchieri Giorgio , Greten Tim 
Published: February 2019

Abstract
Aim: The gut microbiome can modify tumor immunity and has been suggested to be involved in the development and growth of liver cancer as well as metastasis in the liver. However, it remains unknown how the gut microbiome controls hepatic immune responses. This study was designed to exam the effect of the gut microbiome on liver antitumor immunity, and to study potential mechanism.
Experimental Procedure: An antibiotic cocktail containing 0.5g/L vancomycin, 0.5 g/L neomycin and 0.6 g/L primaxin in drinking water was given to reduce mouse gut microbiota. Control mice were kept on regular water. EL4 thymoma cells were injected s.c. to induces spontaneous liver metastasis. B16 melanoma and CT26 colon cancer cells were injected intrasplenically to form liver metastasis. Lung metastasis was induced by tail injection of tumor cells. Spontaneous hepatocellular carcinomas were studied in TRE-MYC mice. Gut bacteria and metabolic studies were performed.
Results: Antibiotic cocktail efficiently depleted gut bacteria. Removing gut commensal bacteria did not affect the growth of primary s.c. EL4 tumors, but impaired formation of liver metastasis in different models. The inhibitory effect on liver metastasis by removing gut microbiome was found after intrasplenic injection of tumor cells to form liver metastasis using both B16 melanoma and CT26 colon cancer tumor cells as well as in TRE-MYC mice. Interestingly, formation of lung metastasis caused by tail vein injection of B16 cells was not impaired by antibiotics treatment, suggesting a liver specific effect. The inhibition of liver metastasis by antibiotic treatment was absent in Rag1 knockout mice, suggesting that the observed mechanism is mediated by the adaptive immune system. A detailed mechanism how the gut microbiome causes metabolic liver changes and thereby growth of liver tumors will be presented.
Conclusion: Our results suggest that the gut microbiome affects the liver immune microenvironment and modulates antitumor immunity
Citation Format: Chi Ma, Miaojun Han, Bernd Heinrich, Qiong Fu, Qianfei Zhang, Xin W. Wang, Giorgio Trinchieri, Tim Greten. Gut microbiome controls growth of liver tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A02.
Abstract A08: Combination with a novel STING agonist significantly improves efficacy of anti-PD1 therapy in mouse syngeneic tumor models
Authors: Perera Samanthi A. , Kopinja Johnny E. , Ma Yanhong , Laskey Jason , Chakravarthy Kalyan , Cui Long , Chen Yiping , Presland Jeremy , Sharma Sharad , Zhao Shuxia , Piesvaux Jennifer , Minnihan Ellen C. , Ferguson Heidi , Woo Hyun Chong , Knemeyer Ian , Kariv Ilona , Tse Archie , Cemerski Saso , Cumming Jared , Trotter B. Wesley , Pan Bo-Sheng , Addona George H. , Long Brian J. 
Published: February 2019

Abstract
Activated STING (STimulator of INterferon Genes) bound to its natural ligand 2,3-cGAMP (cyclic guanosine-adenosine monophosphate), initiates type I interferon (IFN) and pro-inflammatory cytokine production. IFN upregulation is essential to promote antigen-specific CD8+ T-cell priming and leads to potent anti-tumor activity. To exploit this mechanism we synthesized a new STING agonist, MSA-1, that potently activates both mouse and human STING. Intratumoral (IT) administration of MSA-1 to MC38 syngeneic tumor-bearing mice increased tumor and plasma cytokine levels and was effective at driving complete responses (CRs) in 100% of the animals. Most surviving animals developed tumor-specific adaptive immune memory as demonstrated by robust protection against re-challenge with the same tumor type. Mechanistic studies in immune-deficient mice suggested that the initial antitumor activity is in part due to cytokine-driven cytotoxicity and/or other innate immune mechanisms, which may have contributed to some animals not developing an adaptive immune memory. Importantly, MSA-1 caused long-term tumor regressions or CRs in CT26 and B16-F10 tumor models, both of which are intrinsically resistant to single-agent therapy with a fully murinized anti-mouse PD-1 antibody (muDX400). The antitumor immune response in these models was further enhanced when treating the animals with MSA-1 in combination with muDX400. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single agent anti-PD-1 therapy.
Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Long Cui, Yiping Chen, Jeremy Presland, Sharad Sharma, Shuxia Zhao, Jennifer Piesvaux, Ellen C. Minnihan, Heidi Ferguson, Hyun Chong Woo, Ian Knemeyer, Ilona Kariv, Archie Tse, Saso Cemerski, Jared Cumming, B. Wesley Trotter, Bo-Sheng Pan, George H. Addona, Brian J. Long. Combination with a novel STING agonist significantly improves efficacy of anti-PD1 therapy in mouse syngeneic tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A08.
Abstract A11: Ipilimumab protects T cells from the antiproliferative effects of dexamethasone
Authors: Giles Amber J. , Hutchinson Marsha-Kay N.M. , Sonnemann Heather , Reid Caitlin M. , Jung Jinkyu , Zhang Wei , Song Hua , Bailey Rolanda , Davis Dionne , Park Deric M. , Roederer Mario , Gilbert Mark R. 
Published: February 2019

Abstract
Background: Checkpoint inhibitor blockade, designed to activate antitumor immune cells, is gaining enthusiasm as a potential treatment modality for patients with brain tumors. However, adjuvant therapies aimed at killing tumor (i.e., chemotherapy) or reducing tumor-related edema (i.e., corticosteroids) are often cytotoxic to lymphocytes. Yet, whether tumor-specific T cells are harmed during corticosteroid treatment is not known.
Methods: The effects of dexamethasone on healthy donor T cells was tested in vitro for T cell proliferation, cell cycle analysis, glucose uptake, transcriptional changes, and protein expression. The effects of dexamethasone and CTLA-4 antibody blockade were tested in vivo using the GL261 murine glioblastoma model.
Results: Here we show that dexamethasone blocks proliferation of naïve human T cells but not memory T cells. We find that dexamethasone inhibits early stages of T cell proliferation by impairing CD28-mediated cell cycle entry. Dexamethasone induced a fourfold increase in surface CTLA-4 during T cell stimulation, and neutralizing CTLA-4 with ipilimumab overcame the dexamethasone-induced blockade of cell cycle entry in vitro. Further, CTLA-4 blockade in combination with dexamethasone provided a survival benefit in vivo to mice bearing orthotopic GL261 brain tumors. Intriguingly, early dexamethasone treatment afforded the greatest survival advantage
Conclusions: These findings shed light on the T cell-specific effects of dexamethasone and suggest that antigen-experienced T cells are resistant to anti-proliferative effects of corticosteroids. These findings have important implications for patients receiving immune therapy who may benefit from the anti-inflammatory properties of dexamethasone.
Citation Format: Amber J. Giles, Marsha-Kay N.M. Hutchinson, Heather Sonnemann, Caitlin M. Reid, Jinkyu Jung, Wei Zhang, Hua Song, Rolanda Bailey, Dionne Davis, Deric M. Park, Mario Roederer, Mark R. Gilbert. Ipilimumab protects T cells from the antiproliferative effects of dexamethasone [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A11.
Abstract A16: Epstein-Barr virus encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B cell lymphomas
Authors: Eleni Anastasiadou , Dina Stroopinsky , Alimperti Stella , Jiao Alan , Pyzer Athalia , Cipitelli Claudia , Severa Martina , Chen Christopher S. , Uccini Stefania , Avigan David , Faggioni Alberto , Trivedi Pankaj , Slack Frank J. 
Published: February 2019

Abstract
Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Indeed, Epstein-Barr virus (EBV) positive Hodgkin’s lymphoma and gastric adenocarcinomas have higher Programmed Cell Death Ligand, PD-L1, expression. However, how EBV alters ICs in the context of its preferred host, the B lymphocyte and lymphomas, is unknown. Here, we used Burkitt lymphoma (BL), diffuse large B cell lymphomas (DLBCL) and their EBV infected or EBNA2 transfected derivatives to address this question. EBV latency III cells expressed high levels of PD-L1. In a DLBCL model, we found that EBNA2 but not LMP1 is sufficient to induce PD-L1. The upregulation of PD-L1 was confirmed in estrogen inducible EBNA2 carrying B lymphoma cells. Clinical samples from DLBCL patients showed that EBV infected, latency III cases expressed high levels of PD-L1. The PD-L1 targeting oncosuppressor miR-34a was downregulated in EBNA2 transfected cells. miR-34a reconstitution in EBNA2 expressing DLBCL reduced PD-L1 expression and increased their immunogenicity in 2D mixed lymphocyte reactions (MLR) and 3D microfluidic chip based MLRs. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for diagnosis and combinatorial immunotherapy approaches which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.
Citation Format: Anastasiadou Eleni, Stroopinsky Dina, Stella Alimperti, Alan Jiao, Athalia Pyzer, Claudia Cipitelli, Martina Severa, Christopher S. Chen, Stefania Uccini, David Avigan, Alberto Faggioni, Pankaj Trivedi, Frank J. Slack. Epstein-Barr virus encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B cell lymphomas [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A16.
Abstract A19: PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor
Authors: Pauken Kristen E. , Juneja Vikram R. , Sage Peter T. , LaFleur Martin W. , Kuchroo Juhi R. , Ringel Alison , Ron-Harel Noga , Maleri Seth P. , Freeman Gordon J. , Chevrier Nicolas , Haigis Marcia C. , Sharpe Arlene H. 
Published: February 2019

Abstract
Although PD-1 pathway inhibitors are revolutionizing cancer treatment, the mechanisms by which PD-1 regulates anti-tumor immunity are not fully understood. Following subcutaneous transplantation of MC38 adenocarcinoma tumor cells into mice, we show that complete loss of PD-1 selectively on CD8+ T cells improved metabolic activity and functions in the tumor microenvironment (TME). Since clinically PD-1 inhibitors likely act on T cells post-priming, we next deleted PD-1 after initial priming and restricted deletion to roughly 50% of cells. Loss of PD-1 led to T cell-intrinsic boosts in metabolism and CD8+ T cells that lost PD-1 after priming preferentially formed anti-tumor memory cells, suggesting PD-1 antagonizes memory formation. Unexpectedly, there was also a bystander effect that improved functions of PD-1 expressing CD8+ T cells in the TME. These data suggest that complete loss of PD-1 is not necessary for optimal tumor immunity, and that enhancing the functions of a subset of CD8+ T cells can promote an antitumor microenvironment and immunologic memory.
Citation Format: Kristen E. Pauken, Vikram R. Juneja, Peter T. Sage, Martin W. LaFleur, Juhi R. Kuchroo, Alison Ringel, Noga Ron-Harel, Seth P. Maleri, Gordon J. Freeman, Nicolas Chevrier, Marcia C. Haigis, Arlene H. Sharpe. PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A19.
Abstract A26: De novo epigenetic programming restrains PD-1 blockade-mediated T cell rejuvenation
Authors: Ghoneim Hazem E. , Fan Yiping , Moustaki Ardiana , Abdelsamed Hossam , Dash Pradyot , Dogra Pranay , Carter Robert , Awad Walid , Neale Geoff , Thomas Paul G. , Youngblood Ben 
Published: February 2019

Abstract
Immune checkpoint blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. Given that many of the impaired effector properties of terminally exhausted CD8 T cells appear to be heritably maintained even in the absence of antigen, we investigated the role of de novo DNA methylation programming as a cell-intrinsic mechanism for establishing the ICB-nonresponsive state of T-cell exhaustion. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells. Therapeutic approaches to reverse these programs can enhance ICB-mediated T cell rejuvenation and ultimately facilitate the control of chronic viral infections and tumor growth. These data establish de novo DNA methylation programming as a regulator of T cell exhaustion and barrier of ICB therapy.
Citation Format: Hazem E. Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul G. Thomas, Ben Youngblood. De novo epigenetic programming restrains PD-1 blockade-mediated T cell rejuvenation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A26.
Abstract A79: Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of antigen-presenting cells and tumor antigen-specific CTLs
Authors: Brown Michael C. , Holl Eda K. , Boczkowski David , Dobrikova Elena , Mosaheb Mubeen , Chandramohan Vidya , Bigner Darell D. , Gromeier Matthias , Nair Smita K. 
Published: February 2019

Abstract
The tumor microenvironment favors tumor immune escape by suppressing production, activation and/or function of antitumor T cells. Our group has developed a recombinant Rhino-Poliovirus chimera, PVSRIPO, currently being evaluated in Phase-II clinical trial against recurrent glioma. PVSRIPO therapy has afforded durable clinical responses in recurrent glioma patients. Clinical and pre-clinical findings suggest that PVSRIPO primarily acts through an immunological mechanism, rather than via cancer selective cytotoxicity. Here we define the immune adjuvant potential of intratumoral-delivered PVSRIPO that ultimately leads to the engagement/production of antitumor T cells. Sub-lethal infection of human dendritic cells (DCs) with PVSRIPO yields potent, sustained type I interferon dominant activation. PVSRIPO infection of macrophages induces similar activation; however, virus translation and the resulting type I Interferon/TNF-α production by macrophages is strongly enhanced in the presence of the Th2 cytokine IL-4. Compared to conventional adjuvants, e.g. poly(I:C) and LPS, PVSRIPO stimulation of APCs withstands tumor-associated immunosuppression, particularly in macrophages, and achieves more durable activation of DCs. Therapy of B16 melanoma tumors with PVSRIPO led to early production of type I interferon, IL-12, and IFN-γ; which was associated with the recruitment of neutrophils to the tumor site. Neutrophil influx was followed by DC and T cell infiltration. Mice treated with PVSRIPO developed tumor-antigen specific, cytotoxic T cells that were present in both tumor draining lymph nodes and spleens. These events correlated with delay in tumor growth and increase in survival following PVSRIPO therapy. Thus, PVSRIPO’s immune adjuvancy stimulates canonical innate inflammatory responses within the tumor microenvironment that culminates in tumor antigen-specific T cell responses.
Citation Format: Michael C. Brown, Eda K. Holl, David Boczkowski, Elena Dobrikova, Mubeen Mosaheb, Vidya Chandramohan, Darell D. Bigner, Matthias Gromeier, Smita K. Nair. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of antigen-presenting cells and tumor antigen-specific CTLs [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A79.
Abstract A82: Evaluation of novel immune target in hematologic malignancies
Authors: Matsushita Maiko , Yokoe Shinya , Ozawa Koji , Kanchi Saori , Ichikawa Daiju , Matsuki Eri , Mori Takehiko , Okamoto Shinichiro , Hattori Yutaka 
Published: February 2019

Abstract
Background and Objective: Development of drugs such as tyrosine kinase inhibitors (TKIs), immunomodulatory drugs (IMiDs), or proteasome inhibitors (PIs) have improved survival of hematologic malignancies including chronic myeloid leukemia (CML) and multiple myeloma (MM). However, some patients eventually relapse by discontinuation of the drugs or acquiring resistance to the drugs. Thus, it is crucial to develop novel therapy for cure of these malignancies. CML and MM are considered to be relatively immunogenic diseases among hematologic malignancies and immunotherapy might be useful. Since CML cells or MM cells have few somatic mutations which result in amino acid changes and give rise to neoantigens, checkpoint inhibitors alone may not be sufficient to evoke effective immunity against these cells. Instead, overexpressed antigen may be an attractive therapeutic target. We have identified CXorf48 as a highly expressed antigen in several hematologic malignancies including CML and MM. In this study, we investigated whether CXorf48 could serve as a therapeutic target for CML and MM.
Methods and Results: High expression of CXorf48 gene in CML cells and MM cells was confirmed by quantitative PCR and also patients’ gene data obtained from a public repository. In contrast, BMMNCs cells or PBMNCs from healthy donor did not express CXorf48. We induced CXorf48-specific cytotoxic T lymphocytes (CTLs) by stimulating lymphocytes from healthy donors with HLA-A24:02-restricted CXorf48-derived epitope peptide. ELISpot assay, cytotoxic assay and CD107a mobilization assay showed that these CTLs preferentially recognized CML cells and MM cells. Moreover, we could detect CXorf48-specific CTL in peripheral blood of CML patients who remained in complete molecular remission after cessation of TKIs.
Conclusion: Our data suggest that CXorf48 is a novel therapeutic target of CTLs in CML or MM. Immunotherapy against this antigen, such as vaccination therapy or adoptive T-cell therapy after conventional therapies might be an attractive therapeutic strategy for cure of CML and MM.
Citation Format: Maiko Matsushita, Shinya Yokoe, Koji Ozawa, Saori Kanchi, Daiju Ichikawa, Eri Matsuki, Takehiko Mori, Shinichiro Okamoto, Yutaka Hattori. Evaluation of novel immune target in hematologic malignancies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A82.
Abstract B03: RNAi-mediated β-catenin inhibition sensitizes noninflamed tumors to immune checkpoint blockade
Authors: Ganesh Shanthi , Shui Serena , Wang Weimin , Brown Bob D. , Abrams Marc 
Published: February 2019

Abstract
Anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies are immunotherapeutics which confer benefit to several subpopulations of cancer patients, yet the majority of tumors remain insensitive. Wnt/β-catenin signaling has been strongly implicated in mediating cancer immune evasion and resistance to immune checkpoint therapy. The mechanism by which Wnt/β-catenin signaling causes checkpoint resistance is believed to involve blocking of specific cytokines which trigger immune cell recruitment to the tumor, resulting in the phenomenon of T-cell exclusion and rendering the tumor to a non-inflamed state. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines. DCR-BCAT is an advanced experimental therapeutic containing a chemically-optimized RNA interference (RNAi) trigger targeting CTNNB1, the gene that encodes β-catenin, formulated in a tumor-selective lipid nanoparticle. To understand the role of β-catenin in immunotherapy, we investigated DCR-BCAT in combination with checkpoint inhibitors in syngeneic murine tumor allograft models. β-catenin inhibition promoted T-cell infiltration and significantly improved sensitivity to anti-PD-1 and anti-CTLA-4 therapy. The combination treatment yielded significant tumor growth inhibition compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma and Renca renal adenocarcinoma. T-cell mediated cytotoxicity was identified of the primary mechanism of efficacy, as shown by granzyme B and perforin staining. Interestingly, antitumor efficacy in these combination studies was not correlated with Wnt activation status in syngeneic models. Finally and strikingly, when DCR-BCAT was combined with immuotherapy in mice which develop spontaneous Wnt-driven mammary tumors, checkpoint therapy potentiation yielded complete tumor regressions. These data offer proof-of-concept for conversion of non-inflamed tumors to inflamed tumors by β-catenin inhibition, and support clinical evaluation of this combination approach using a first-in-class RNAi-based agent.
Citation Format: Shanthi Ganesh, Serena Shui, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-mediated β-catenin inhibition sensitizes noninflamed tumors to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B03.