bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A123: Modulation of immune cell trafficking into human colorectal cancer by gut microbiota
Authors: Cremonesi Eleonora , Amicarella Francesca , Garzon Jesus Francisco Glaus , Governa Valeria , Muraro Manuele Giuseppe , Mele Valentina , Padovan Elisabetta , Oertli Daniel , Zajac Paul , Spagnoli Giulio Cesare , Borsig Lubor , Iezzi Giandomenica 
Published: November 2016

Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death. CRC infiltration by immune cells, including cytotoxic CD8+ T cells (CTLs), IFN-gamma-producing T-helper 1 cells (Th1), Foxp3+ regulatory T cells (Tregs) and CD16+ MPO+ neutrophils, is associated with favorable prognosis. However, chemokines driving these cell populations into the tumor site, their cellular sources and their microenvironmental triggers remain to be elucidated. We investigated the chemokine/chemokine receptor network promoting CRC infiltration by immune cells associated to favorable prognosis. Analysis of freshly excised specimens of CRC and adjacent healthy colonic tissues revealed that tumor infiltration by beneficial immune cells is associated with the expression of four main chemokine patterns: 1) CCL3, CCL5, CCL8, CXCL9, CXCL10, and CXCL12 for CTLs; 2) CCL5, CCL22, CXCL9 and CXCL12 correlating with CRC infiltration by Th1; 3) CCL22 and CXCL12 attracting Tregs; 4) CXCL2 and CXCL5, promoting chemotaxis of CD16+ MPO+ myeloid cells. Most of identified chemokines were found to be expressed, although at different levels, in primary CRC cells purified from tumor specimens and from xenografts generated upon injection of CRC cells in immunodeficient mice. Notably, chemokine expression levels in orthotopic xenografts, developed upon intracecal injection of tumor cells, were significantly higher as compared to those of subcutaneous tumors. Antibiotic treatment of tumor bearing mice drastically reduced chemokine expression in orthotopic xenografts, thus suggesting a role for commensal bacteria in chemokines induction in tumor cells. Importantly, human CRC samples characterized by high expression of chemokine and immune cell markers, displayed significantly higher bacterial loads, as compared to samples showing low chemokine expression and immune cell infiltration. Furthermore, bacterial loads significantly correlated with expression of CCL3 and CCL5, and Th1 infiltration. These data suggest that stimuli derived from gut flora components may trigger chemokine production in CRC tissues thus leading to tumor infiltration by beneficial immune cells.
Note: This abstract was not presented at the conference.
Citation Format: Eleonora Cremonesi, Francesca Amicarella, Jesus Francisco Glaus Garzon, Valeria Governa, Manuele Giuseppe Muraro, Valentina Mele, Elisabetta Padovan, Daniel Oertli, Paul Zajac, Giulio Cesare Spagnoli, Lubor Borsig, Giandomenica Iezzi. Modulation of immune cell trafficking into human colorectal cancer by gut microbiota [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 A123.
Abstract A129: Ablation of neuropilin 1 from glioma associated macrophages and microglia slows tumor progression
Authors: Miyauchi Jeremy T. , Chen Danling , Choi Matthew , Nissen Jillian , Shroyer Kenneth , Selwood David , Tsirka Stella E. 
Published: November 2016

Abstract
Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Moreover, transplanting bone marrow from mice with Nrp1-deficient macrophages to wild type recipient mice led to reductions in tumor growth, al-be-it not to the extent seen in knockout mice. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression.
Citation Format: Jeremy T. Miyauchi, Danling Chen, Matthew Choi, Jillian Nissen, Kenneth Shroyer, David Selwood, Stella E. Tsirka. Ablation of neuropilin 1 from glioma associated macrophages and microglia slows tumor progression [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 A129.
Abstract A138: Increased CD3(+) cell infiltration during pancreatic intraepithelial neoplasia progression in KrasG12D/Pdx1-Cre transgenic mouse model
Authors: Hong Xiafei , Dai Hongmei , Wang Xianze , Tian Feng , Wu Wenming , Zhao Yupei 
Published: November 2016

Abstract
This study aim to quantify the dynamic number changes of CD3(+) lymph cells in a pre-malignant stage of pancreatic cancer, namely, pancreatic intraepithelial neoplasia (PanIN). The experiment was conducted using a well-established KrasG12D/Pdx1-Cre transgenic mouse model. The animal model expressed a pancreas-specific active KrasG12D gene, resulting in PanIN progression and acinar structure loss in a time dependent manner. Experiment mice were sacrificed at 5, 7, 9, and 11 months (n = 3 for each time point). The pancreas tissues were fixed and stained by a rabbit monoclonal [EPR4517] to CD3G (Abcam Cat#: ab134096, 1:500 dilution). The CD3(+) lymph cell number were quantified by Leica optical system and the CD3(+) lymph cells were manually counted (ten fields for each mouse). All experimental conducted were approved by the ethical committee. The CD3(+) lymph cell number was calculated by averaging all field in each time point (thirty fields per time point). The number was then presented as mean ± SEM. Quantitatively, the CD3(+) cell were 11.73 ± 2.83, 14.23 ± 2.07, 14.90 ± 1.99, and 29.13 ± 2.04 per field in 5, 7, 9, and 11 month-old mice. The CD3(+) cell number was not significantly different among 5, 7, and 9 month-old mice. However, the number significantly increase in the 11 month-old mice compared with the 9-month ones (P&lt; 0.0001, unpaired t-test). We observed that CD3(+) lymph cells were predominately present in PanIN area, while almost not observable in the remaining normal acinar area. The phenomenon that CD3(+) lymph cells infiltrate in PanIN area indicates that this type of immune cells may involve in PanIN progression.
Citation Format: Xiafei Hong, Hongmei Dai, Xianze Wang, Feng Tian, Wenming Wu, Yupei Zhao. Increased CD3(+) cell infiltration during pancreatic intraepithelial neoplasia progression in KrasG12D/Pdx1-Cre transgenic mouse model [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 A138.
Abstract B014: Improved therapeutic activity of agonistic, human anti-CD40 monoclonal Abs by selective Fc receptor-engagement
Authors: Dahan Rony , Ravetch Jeffrey V. 
Published: November 2016

Abstract
The use of immunomodulatory mAbs to stimulate effective therapeutic anticancer immunity has shown clinical successes for the treatment of an increasing number of cancer types. An approach that is currently under clinical development uses agonistic anti-CD40 mAbs to induce APC activation, thereby harnessing the potency of the immune response to eradicate tumors. While engagement of the inhibitory Fcγ Receptor(FcγR)IIB is required for the in vivo agonistic activity of anti-mouse CD40 mAbs, a similar requirement for human mAbs has been disputed based on in vitro studies and in vivo studies performed either in wild-type or mouse FcγR knockout strains and thus fails to address the unique binding affinities and tissue distribution of human FcγRs. To overcome these limitations we generated and used unique mouse model fully humanized for its FcγRs and CD40, and revealed that FcγRIIB engagement is also essential for the activity of the human CD40 agonistic mAbs, including CP-870,893, while engagement of the activating FcγRIIA inhibits their activity. By engineering Fc variants of human mAbs with selective enhancement to FcγRIIB but not to FcγRIIA, significant improvement of antitumor immunity was observed in multiple tumor models. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using an appropriate pre-clinical model that accurately reflects the unique affinities and cellular expression of human FcRs, thus providing a development approach for therapeutic human antibodies based on their requirement for selective FcγR interactions. Here we describe the selection of optimized next-generation Fc-engineered agonistic CD40 mAbs.
Citation Format: Rony Dahan, Jeffrey V. Ravetch. Improved therapeutic activity of agonistic, human anti-CD40 monoclonal Abs by selective Fc receptor-engagement [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 B014.
Abstract B019: LAG3 is an immunotherapeutic target in murine triple negative breast cancers whose activity is significantly enhanced in combination with phosphatidylserine targeting antibodies
Authors: Gray Michael J. , Gong Jian , Hutchins Jeff , Freimark Bruce 
Published: November 2016

Abstract
Previous pre-clinical modeling demonstrated that phosphatidylserine (PS) targeting antibodies are capable of significantly enhancing the effectiveness of anti- programmed cell death ligand 1 (PD-1) therapy in murine breast cancers (BC). These results prompted our hypothesis that PS blocking antibodies should also be capable of enhancing the activity of additional immunotherapies in BC, including triple negative breast cancer (TNBC). PS normally resides in the inner leaflet of the plasma membrane in most cell types. Conditions that promote cellular stress in the tumor microenvironment, such as reactive oxygen species (ROS), hypoxia, and irradiation, cause PS externalization and exposure on tumor associated endothelial cells and tumor cells, where it is recognized by specific receptors, including members of the TIM and TAM family. This PS recognition promotes an innate system driven immunosuppressive condition by promoting an influx of myeloid derived suppressor cells (MDSCs), an M2-macrophage shift, and suppression of dendritic cell maturation, while inducing anti-inflammatory cytokines. To identify additional immuno-therapeutic targets that may be potential targets for combinational treatment with PS-targeting antibodies, we employed gene expression analysis on tumors from murine TNBC treated with single and combinations of PS and PD-1 targeting antibodies. Of the genes assayed, expression of the lymphocyte activation gene 3 (LAG3) increased in each treatment arm, suggesting it may be a potential target for combinational therapy in breast cancers. To test our hypothesis, C57BL/6 mice hosting the murine TNBC line E0771 were treated with a PS targeting antibody or a LAG3 targeting antibody alone or in combination. Our data demonstrate that while PS-blocking and anti-LAG3 therapies each have moderate efficacy as single agents, combinational treatment significantly impeded the growth of TNBC, and was capable of increasing tumor infiltrating lymphocytes (TILs), including CD8 + and CD3 + T-cells, and reducing the percentage of MDSCs over that observed by single treatments. Combined, our data demonstrate that LAG3 targeting also represents a viable option for the treatment of TNBC, and that the addition of PS targeting antibodies to LAG3 therapy can effectively increase the anti-tumor and immune-activating effects mediated by multiple checkpoint therapies.
Citation Format: Michael J. Gray, Jian Gong, Jeff Hutchins, Bruce Freimark. LAG3 is an immunotherapeutic target in murine triple negative breast cancers whose activity is significantly enhanced in combination with phosphatidylserine targeting 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 B019.
Abstract B044: Patient-specific immunotherapy through TCR gene transfer
Authors: Fanchi Lorenzo F. , Bies Laura , Song Ji-Ying , Linnemann Carsten , Schumacher Ton 
Published: November 2016

Abstract
Adoptive cell transfer (ACT) of autologous ex vivo expanded tumor-infiltrating lymphocytes has shown to mediate significant tumor regression in metastatic melanoma. This finding has demonstrated the capacity of endogenous T cells to mount an immune response against and eliminate cancer cells. Two clinically relevant approaches to adoptive cell transfer are ACT of expanded TIL and ACT of gene-modified peripheral blood lymphocytes (PBLs). The former approach consists of isolation of tumor-infiltrating lymphocytes from tumor biopsies, ex vivo expansion and re-infusion after treatment with a lymphodepleting regimen. In the latter, PBLs are engineered to express T-cell receptors (TCRs) recognizing common melanoma tumor antigens. While both approaches have shown different extents of clinical benefit, several limitations hamper clinical efficacy.
T cell specificity, phenotype and differentiation state of ex vivo expanded TIL are largely unknown, while ACT of gene-modified lymphocytes is limited by the use of TCRs recognizing common tumor antigens, which can be differentially expressed between patients. Furthermore, the use of these TCRs is often limited to a handful of HLA types. These factors can lead to reduced therapeutic efficacy and applicability.
Here we aim to compare the tumor control of T cells expressing ‘personalized’ tumor-reactive TCRs and expanded tumor-infiltrating lymphocytes after adoptive cell transfer in a xenograft mouse model. To this end, highly tumor-reactive T cell receptors are isolated from TIL on a per-patient basis. These TCRs are introduced into donor peripheral blood lymphocytes, forming a population of tumor-reactive cells tailored to the patient tumor. These cells are subsequently tested for efficacy in a xenograft mouse model bearing autologous (patient-derived) tumor.
Using the outlined approach, we aim to identify determinants of therapy efficacy. Preliminary results have shown dramatic tumor regression after ACT of patient-specific gene-modified T cells, leading to complete remission of tumors in all treated mice. In contrast, tumors of mice treated with TIL or control T cells did not show significant reduction of tumor burden, when compared to untreated controls.
Citation Format: Lorenzo F. Fanchi, Laura Bies, Ji-Ying Song, Carsten Linnemann, Ton Schumacher. Patient-specific immunotherapy through TCR gene transfer [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 B044.
Abstract B051: Super cross-presentation of tumor antigens by synthetic design of an anti-phosphatidylserine bridge protein
Authors: Corey Daniel , Ring Aaron , McCracken Melissa , Miyanishi Masanori , Gordon Sydney , Weissman Irving 
Published: November 2016

Abstract
Cell loss by apoptosis is a common feature in tumors. Dying tumor cells induce immune tolerance within the tumor microenvironment largely through highly conserved homeostatic clearance programs that restore tissue immune homeostasis and contribute to the formation of an immunosuppressive niche. The translocation of phosphatidylserine (PS) on cellular membranes, during the initial phases of apoptosis, functions as a recognition and removal signal that limits the immunogenicity of cell death. We examined whether altering clearance of dying cancer cells to elicit inflammatory turnover can allow for and potentiate immune responses against tumor cells. To remove inhibitory signals in the homeostatic clearance pathway we utilized a molecular bridge scaffold to engineer a modified phosphatidylserine bridge protein (FA58C2-hIgG1 or C2-hIgG1) that works as a bridge between apoptotic cells expressing aminophospholipids and phagocytes bearing Fc receptors. In vivo administration of C2-hIgG1 partially restores immune responses to dead tumor cells in antigen cross presentation assays and promotes recruitment and retention of tumor antigen specific CD8+ T cells, dendritic cells, and natural killer cells into tumors. These effects combine to elicit anti-lymphoma immunity, improve responses to immune checkpoint inhibitors, and enhance the effectiveness of adoptive T cell transfers using engineered T Cell Receptors (TCRs) but not chimeric antigen receptor engineered (CAR-T) T cells.
Citation Format: Daniel Corey, Aaron Ring, Melissa McCracken, Masanori Miyanishi, Sydney Gordon, Irving Weissman. Super cross-presentation of tumor antigens by synthetic design of an anti-phosphatidylserine bridge protein [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 B051.
Abstract B062: Immune activation by LMP1 CD40 pathway and LMP1-IPS-1 STING pathway activators
Authors: Kornbluth Richard S. , Gupta Sachin , Termini James M. , Guirado Elizabeth , Stone Geoffrey W. 
Published: November 2016

Abstract
The strongest CD8+ T cell responses ever recorded in humans occur as a result of infection by the Epstein-Barr Virus (EBV). Following a massive CD8+ T cell response during acute EBV infection, ∼5.5% of the total CD8+ T cell repertoire in blood is thereafter committed to the life-long suppression of viral replication. The key to this response is the EBV Latent Membrane Protein-1 (LMP1) which functions as a constitutively activated form of the CD40 receptor. LMP1 consists of an N-terminal domain that clusters in cell membranes and a C-terminal domain that engages the proteins of the CD40 signalosome. Studies to determine if LMP1 could be used for immunotherapy led to the following conclusions: (1) LMP1 mRNA directly activated human dendritic cells (DCs), showing its potential as an adjuvant for mRNA vaccines; (2) Adenovirus (Ad)-delivered LMP1 strongly enhanced vaccine-induced CD8+ T cell responses in mice, indicating that LMP1 may enhance Ad-based oncolytic therapies; (3) lentiviruses incorporating LMP1 became strong activators of DCs in vitro; and (4) DNA vaccines incorporating LMP1 protected mice from tumor challenge in a B16F10 melanoma metastasis model. These data show that the LMP1 nucleic acid sequence is a portable genetic adjuvant with broad applicability to tumor immunotherapy. In related studies, the membrane clustering N-terminal domain of LMP1 was fused to Interferon-beta Promoting Stimulator-1 (IPS-1, also called MAVS, VISA, or Cardif), a protein that requires membrane clustering to become activated. This fusion protein acts independently of cyclic dinucleotides (CDN) to activate downstream mediators of the STING pathway. Vaccination of mice with Ad expressing antigen plus LMP1-IPS-1 resulted in complete protection from challenge with Vaccinia-antigen virus (&gt;1 million-fold protection). These data suggest that LMP1-IPS-1 combined with gene delivery technologies may supplant the need for small molecule CDNs for STING pathway activation in immuno-oncology.
Citation Format: Richard S. Kornbluth, Sachin Gupta, James M. Termini, Elizabeth Guirado, Geoffrey W. Stone. Immune activation by LMP1 CD40 pathway and LMP1-IPS-1 STING pathway activators [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 B062.
Abstract B065: Use of simultaneous detection of externalized CD107a and CD137 for evaluation of specificity and effector functions of polyclonal T-cells produced for adoptive cellular immunotherapy of prostate cancer
Authors: Taborska Pavla , Stakheev Dmitry , Vavrova Katerina , Vrabcova Petra , Bartunkova Jirina , Smrz Daniel 
Published: November 2016

Abstract
The ex vivo production of T-cells that can recognize tumor-associated antigens (TAAs) and through this recognition eliminate cancer cells is the goal of T-cell-based adoptive cellular immunotherapy (ACI). The technological approaches that use whole cancer cells or their pertinent lysates as a source of TAAs for production of these T-cells lead to generation of polyclonal T-cells their antigen specificity of which is often unknown. Evaluation of such polyclonal T-cells is therefore challenging because their target and off-target performance might be difficult to predict. In our study we used human dendritic cells (DCs) pulsed with inactivated prostate cancer cell line LNCaP and matured with polyinosinic:polycytidylic acid (poly(I:C)) to induce expansion of autologous lymphocytes. The expanded lymphocytes were then challenged with live LNCaP cells and analyzed by simultaneous detection of a marker of T-cell cytotoxicity and antigen-induced T-cell stimulation, the surface externalization of, respectively, CD107a and CD137. Our data showed that lymphocytes expanded with LNCaP-pulsed and poly(I:C)-matured DCs contained a notable fraction of CD137 and/or CD107a positive T-cells after their challenge with live LNCaP cells. No such notable fraction was however observed in resting lymphocytes, or when the lymphocytes were challenged with ovarian cancer cell line SKOV-3. Importantly, autologous lymphocytes that were expanded with poly(I:C)-matured DCs not previously pulsed with the inactivated LNCaP cells did not show a notable population of the marker positive cells. Collectively, our data showed that simultaneous detection of externalized CD107a and CD137 on the surface of polyclonal T-cells may allow for evaluation of polyclonal T-cell specificity and effector functions after their challenge with complex antigens.
Citation Format: Pavla Taborska, Dmitry Stakheev, Katerina Vavrova, Petra Vrabcova, Jirina Bartunkova, Daniel Smrz. Use of simultaneous detection of externalized CD107a and CD137 for evaluation of specificity and effector functions of polyclonal T-cells produced for adoptive cellular immunotherapy of prostate 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 B065.