bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A067: Quality of initial activation of CD8 T cells specific for TRP1 determines long-term antitumor immunity
Authors: Tyler Paul , Servos Mariah , Dougan Stephanie K. 
Published: May 2016

Abstract
We used somatic cell nuclear transfer to generate two independent lines of transnuclear mice from CD8 T cells recognizing the endogenous melanoma antigen TRP1. These two lines, while having the same specificity, differ by 100 fold in their affinity for antigen. We previously reported that activated CD8 T cells from either TRP1high or TRP1low mouse lines have anti-tumor activity in vitro and can slow the progression of B16 melanoma in vivo to similar extents, suggesting that TCR affinity is not necessarily correlated with anti-tumor function.
Here we first analyzed the mechanism of tumor control in our TRP1 model. In tumor-bearing mice receiving activated TRP1 cells by adoptive transfer, we examined tumor infiltrates and found 1) an increase in the CD8:Foxp3 ratio; 2) a decrease in myeloid suppressor cells; and 3) greatly increased expression of MHC class I and class II expression by the B16 tumor cells. B16 cells upregulate MHC expression in vitro in response to IFNγ; thus, we hypothesize that MHC expression on B16 cells in mice receiving TRP1 adoptive cell therapy is a signature of IFNγ production in the tumor.
We further used a panel of altered peptide ligands to extend the range of TCR activation potentials in our TRP1 model. One ligand, K8, binds poorly to MHC class I yet stimulates robust proliferation, cytotoxicity and cytokine production from both TRP1high and TRP1low cells. Interestingly, K8-activated TRP1high and TRP1low cells fail to upregulate PD-1 expression. When adoptively transferred into tumor-bearing mice, K8-activated TRP1 cells delayed tumor growth to a similar extent as TRP1 cells activated by the reference peptide, yet mice receiving K8-activated cells had an increased chance of developing long-term memory. We show TRP1 tetramer+ CD44+ CD8+ T cells in K8-treated mice that survived both primary and secondary challenge with B16. Transcriptional profiling of K8 versus reference peptide activated TRP1 cells reveals a transcriptional program associated with anti-tumor immunity.
Citation Format: Paul Tyler, Mariah Servos, Stephanie K. Dougan. Quality of initial activation of CD8 T cells specific for TRP1 determines long-term antitumor immunity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A067.
Abstract A068: Imbalance in regulatory T (Treg) cells frequency in peripheral circulation of patients with oral squamous cell carcinoma and their effects on growth of oral cancer
Authors: Aggarwal Sadhna , Das Satya N. , Sharma Suresh C. 
Published: May 2016

Abstract
Regulatory T (Treg) cells play a major role in establishment and maintenance of self tolerance of immune system. Deficit in the numbers of Tregs contributes to the development of autoimmune diseases, allergy and graft rejection whereas abundance of Tregs suppresses anti-tumour immune response leading to tumour immuno-evasion. In this study, we have estimated the frequency of distinct immune cells, Tregs and its phenotypic subsets in patients with Oral Squamous Cell Carcinoma (OSCC) by multicolour flowcytometry. Subsequently we investigated the effects of MACS sorted Tregs on growth/proliferation/angiogenesis of OSCC cell lines in vitro.
Frequency of all the effector type anti-tumour immune cells such as CD8+ T-cells, NK (CD56+) and NKT (CD3+CD56+) cells was found to be decreased whereas CD3+, CD4+, γδ-T cells were upregulated in OSCC patients. We observed significantly increased (p &lt; 0.05) prevalence of Tregs and their phenotypic subsets (CD4+CD25+, CD4+FoxP3+, CD8+FoxP3+, CD4+CD25+FoxP3+) in peripheral circulation of OSCC patients as compared to that of the normal individuals. Our study further showed a definite association between the OSCC progression and elevated Tregs frequency. An association between reciprocally regulated Treg and Th17 cells was also observed. The increased frequency of CD4+CD8+CD25+FoxP3+, a unique T cells subset was seen in OSCC patients. The CTLA-4+ and GITR+ Tregs also showed higher occurrence in patients indicating their contribution to the immuno-suppressive function of Tregs in OSCC. Introduction of MACS isolated Treg cells to in vitro oral cancer cell culture resulted in increased proliferation and expression of angiogenic marker VEGF by cancer cells showing that these suppressor cells helps in growth and proliferation of OSCC cells.
Accumulation of heterogeneous subsets of Tregs in the peripheral circulation indicates their suggestive role in tumour induced immuno-suppression as well as in growth and proliferation of oral cancer cells. Therefore, inhibitory manipulation of Tregs, in terms of their frequency and functional activity, can be added to the therapeutic armamentarium for enhancing anti-tumour immunity in OSCC patients and preventing the establishment and progression of oral cancer.
Citation Format: Sadhna Aggarwal, Satya N. Das, Suresh C. Sharma. Imbalance in regulatory T (Treg) cells frequency in peripheral circulation of patients with oral squamous cell carcinoma and their effects on growth of oral cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A068.
Abstract A078: Computational discovery and experimental validation of novel drug targets in immuno-oncology
Authors: Machlenkin Arthur , Levy Ofer , Rotman Galit 
Published: May 2016

Abstract
The past few years have witnessed a renaissance in the field of immuno-oncology largely due to the clinical success in targeting the immune checkpoints CTLA-4 and PD-1. Towards identification of novel immune checkpoint drug targets we developed a dedicated predictive discovery platform.
The B7/CD28 discovery platform is a predictive model based on genomic and protein features along with expression patterns of known B7/CD28 proteins. The platform has been tested and validated extensively and has demonstrated its validity by identifying non-novel immune checkpoints such as TIGIT and VISTA, which were not used in the design stage.
The B7/CD28 predictive platform was employed to identify 11 new immune checkpoint candidates which are currently in different validation stages. In this poster, we will describe our discovery approach as well as our validation path. In addition, we will present experimental data demonstrating the immuno-modulatory function and expression patterns of several of our novel immune checkpoints. These experimental results serve as an additional confirmation to the accuracy of our B7/CD28 predictive discovery platform and shed light on the therapeutic potential of the novel immune checkpoints identified using this unique discovery approach.
Citation Format: Arthur Machlenkin, Ofer Levy, Galit Rotman. Computational discovery and experimental validation of novel drug targets in immuno-oncology. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A078.
Abstract A087: Phase separation of signaling molecules promotes T cell receptor signal transduction
Authors: Su Xiaolei , Ditlev Jon , Hui Enfu , Banjade Sudeep , Okrut Julia , Taunton Jack , Rosen Mike , Vale Ron 
Published: May 2016

Abstract
Signaling through the T cell receptor (TCR) mediates T cell activation, differentiation, and proliferation. Previous microscopy studies have shown the spatial reorganization of signaling molecules into microclusters on the plasma membrane after TCR activation. However, how microclusters form and what roles these structures play in signal transduction remain unclear. Importantly, direct comparison of the biochemical activities of signaling molecules in the clustered versus unclustered state has been lacking. Here, we address these questions by reconstituting a TCR signaling pathway in vitro with 12 purified proteins, beginning with TCR phosphorylation and culminating in actin polymerization. We show that upon initiation of phosphorylation, multivalent protein-protein interactions drive the phase separation of signaling molecules into microclusters that display liquid-like properties. These clusters enrich kinases but exclude phosphatases, thus sustaining protein phosphorylation. We also directly demonstrate that the reorganization of actin regulatory proteins into these clusters substantially enhances actin filament assembly at the membrane. These results establish that microclusters create unique physical and biochemical environments that promote reactions in TCR signaling. The principles revealed here likely apply to other systems that exploit phase separation to regulate biochemical reactions on membranes, in the cytoplasm, or the nucleus.
Citation Format: Xiaolei Su, Jon Ditlev, Enfu Hui, Sudeep Banjade, Julia Okrut, Jack Taunton, Mike Rosen, Ron Vale. Phase separation of signaling molecules promotes T cell receptor signal transduction. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A087.
Abstract A105: Cross-talk between tumors can affect responses to therapy
Authors: Devaud Christel , Westwood Jennifer A. , John Liza , Yong Carmen S.M. , Beavis Paul A. , Snyder Linda A. , Schwendener Reto A. , Phillip Darcy K. , Kershaw Michael H. 
Published: May 2016

Abstract
Tumors are associated with a microenvironment that can influence responses to immunotherapy. Advanced stages of cancer often involve multiple tumors in different locations in the body. We have demonstrated that the tumor microenvironment can vary with anatomical site, and that normal tissue surrounding the site of tumor implantation can contribute to sculpting the subsequent tumor microenvironment. Furthermore, we demonstrate that tumor responses to immunotherapy, consisting of three agonist antibodies, vary with anatomical site. We also investigated whether tumors and their disparate microenvironment can interact with each other at a distance, in a multiple tumor setting, through a form of cross-talk, to affect their responses to immunotherapy. Our study investigated the cross-talk between two tumors with disparate microenvironments in a mouse model. We demonstrated that immunosuppressive visceral tumors could influence distant subcutaneous (SC) tumors, normally responsive to immunotherapy, to render them resistant. We observed distinct modifications in the SC tumor microenvironment following cross-talk with kidney tumors, which exhibit a type-2 macrophage-related immunosuppressive microenvironment. Indeed, when a concomitant kidney tumor was present in the mouse, the SC tumors were highly infiltrated with M2 macrophages and had a reduced T cell and NK cell effector immune profile. Finally, blocking the M2-associated chemokine CCL2 or depleting macrophages, significantly improved the effect of immunotherapy on SC tumors in the presence of concomitant kidney tumors. This work presents a novel finding describing the potential negative influence that a tumor, with a strong immunosuppressive microenvironment, can exert on distant tumors that would normally be responsive to treatment. This report may lead to a new outlook in the selection and prioritization of treatment of multiple tumors in advanced metastatic cancer, which will consider the anatomical location and corresponding microenvironment of individual tumors.
Citation Format: Christel Devaud, Jennifer A. Westwood, Liza John, Carmen S.M. Yong, Paul A. Beavis, Linda A. Snyder, Reto A. Schwendener, Darcy K. Phillip, Michael H. Kershaw. Cross-talk between tumors can affect responses to therapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A105.
Abstract A110: Mutant MHC class II epitopes drive therapeutic immune responses to cancer
Authors: Vormehr Mathias , Kreiter Sebastian , Roemer Niels van de , Diken Mustafa , Löwer Martin , Vascotto Fulvia , Diekmann Jan , Boegel Sebastian , Schroers Barbara , Tadmor Arbel D. , Türeci Özlem , Sahin Ugur 
Published: May 2016

Abstract
Mutations are regarded as ideal targets for cancer immunotherapy. As neoepitopes with strict lack of expression in any healthy tissue, they are expected to be safe and could bypass the central tolerance mechanisms. Recent advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the readily targeting of mutated neoantigens for personalized cancer vaccination.
We demonstrated in three independent murine tumor models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that unexpectedly the immunogenic mutanome is pre-dominantly recognized by CD4+ T cells. RNA vaccination with such MHC class II restricted immunogenic mutations leads to infiltration of CD4+ and CD8+ T cells into the tumor, reduces intratumoral regulatory T cells and ultimately confers strong anti-tumor activity. Encouraged by these findings we set up a process comprising mutation detection by exome sequencing, selection of vaccine targets by solely bioinformatical prioritization of mutated epitopes predicted to be abundantly expressed and presented on MHC class II molecules. Synthetic mRNA vaccines encoding multiple of these prioritized mutated epitopes induce potent tumor control and complete rejection of established aggressively growing tumors in mice. Moreover, we demonstrate that CD4+ T cell neoepitope vaccination primes CTL responses against an independent immunodominant antigen in tumor bearing mice indicating orchestration of antigen spread. Our findings reveal that cancer mutation based MHC class II restricted epitopes are attractive vaccination targets and provide the preclinical proof of concept for an integrated process from tumor sample to a cancer vaccine customized to the unique repertoire of each patient`s tumor.
Citation Format: Mathias Vormehr, Sebastian Kreiter, Niels van de Roemer, Mustafa Diken, Martin Löwer, Fulvia Vascotto, Jan Diekmann, Sebastian Boegel, Barbara Schroers, Arbel D. Tadmor, Özlem Türeci, Ugur Sahin. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A110.
Abstract A118: Transforming growth factor-beta as a therapeutic target for pancreatic cancer
Authors: Meraz Ismail , Vergara Leoncio , Suki Sarah , Gunamalai Prem Siddharth , Serda Rita Elena 
Published: May 2016

Abstract
Recent evidence supports a strong role for immune suppression in facilitating cancer progression. Transforming growth factor beta (TGFß) regulates a diverse array of biological events, including neoangiogenesis, stromal formation, and immune responses. Both TGFß and a small molecule inhibitor of TGFßR-1, LY364947, were effective regulators of these processes in vitro. Using quantitative RT-PCR and fluorescence imaging, TGFß increased collagen production by pancreatic stellate cells while addition of LY364947 suppressed production below basal levels. Endothelial cell proliferation, measured as a function of endothelial tube formation in Geltrex® matrix, was similarly increased by TGFß and reduced to basal levels by LY364947. To explore the in vivo effects of these molecules, LY364947 was encapsulated in liposomes to encourage tumor accumulation and to avoid administration of DMSO vehicle. Liposomes were prepared with a molar ratio of 6:3:1 1,2-dipalmitoyl-sn-glycero-3-phosphocholine /Chol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] using a Hei-Vap Series Heidolph Rotatory Evaporator and a Thermobarrel Extruder. In contrast to in vitro studies, tumor stromal content in human pancreatic capan-2 tumors established in nude mice was not influenced by LY364947, free or liposomal. In addition, tumor progression, as a function of size, and myeloid populations were unaltered by weekly treatments with liposomal LY364947. Thus the influence of TGFßR-1 inhibition in cell cultures does not translate directly into biologically equivalent events.
Citation Format: Ismail Meraz, Leoncio Vergara, Sarah Suki, Prem Siddharth Gunamalai, Rita Elena Serda. Transforming growth factor-beta as a therapeutic target for pancreatic cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A118.
Abstract A120: Tumor-educated B cells acquire LAP/TGF-β1 and PD-L1 expression and suppress antitumor immune response
Authors: Zhang Yu , Morgan Richard , Chen Chuan , Cai Yancheng , Shin Seung-Uon , Cho Hyun-Mi , Bayati Ahmed Al , Pimental Augustin , Rosenblatt Joseph D. 
Published: May 2016

Abstract
B lymphocytes play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms are poorly understood. EMT-6 mammary tumors grow well in wild type (WT) mice but show reduced growth in B-cell deficient μ-/- BALB/c mice (BCDM). WT mice demonstrate B cell infiltration into the tumor bed and a reduced cytolytic T cell response relative to BCDM. Expression of LAP/TGF-β1, CD80, CD86 and PDL-1 is increased in tumor infiltrating B cells (TIL-B) relative to splenic B cells. LAP/TGF-β1 expression progressively increased from 5.4±1.7% on d8 to 43.1±6.1% of TIL-B by d21 post tumor implantation. Co-culture of EMT-6 tumor cells with naïve B cells generated B cells (EMT6-B) with a similar immunophenotype to TIL-B. Purified TIL-B or in vitro generated EMT6-B markedly suppressed CD4+CD25- T cell proliferation, and Th1 cytokine secretion compared to naïve splenic B cells. Acquired B regulatory function required direct tumor cell: B cell contact, and was partially reversed by antibody to TGF-β1 or PDL-1, leading to tumor rejection in vivo. B cell acquisition of a suppressive phenotype following tumor infiltration may result in profound inhibition of T cell anti-tumor response. Similar B cell mediated immunosuppression may be operative in human solid tumors.
Citation Format: Yu Zhang, Richard Morgan, Chuan Chen, Yancheng Cai, Seung-Uon Shin, Hyun-Mi Cho, Ahmed Al Bayati, Augustin Pimental, Joseph D. Rosenblatt. Tumor-educated B cells acquire LAP/TGF-β1 and PD-L1 expression and suppress antitumor immune response. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A120.
Abstract A123: CD14+ monocyte recruitment, transformation and support of tumor survival in a lung cancer model
Authors: Schenk Erin , Dietz Allan 
Published: May 2016

Abstract
Our previous work has shown that in multiple hematologic and solid malignancies, an increased presence of CD14+HLA-DRlo/neg cells in the peripheral blood are associated with systemic immune suppression and poor prognosis. We have also demonstrated that glioblastoma and non-Hodgkin lymphoma tumor cells can convert healthy donor CD14+ cells into CD14+HLA-DRlo/neg. Thus, a critical step toward the generation of these immune suppressive cells is the recruitment of CD14+ monocytes to the tumor. In this study we investigated the mechanism for monocyte recruitment by lung cancer cell lines, the effect these lines have on the monocytes, and the effect the monocytes have on the tumor. Monocyte recruitment by H23, a human lung adenocarcinoma cell line, was studied using freshly isolated CD14+ cells and measured in real time with live cell imaging. Monocytes from 10 of 10 unique healthy donors robustly migrated towards H23 supernatant in a dose dependent fashion. H23 produces CCL2 at levels of 9160 ± 1615 pg/mL measured by ELISA in addition to elaborating the monocyte recruitment factors CXCL1 and IL-8 seen by cytokine array. A 2 day co-culture of H23 with monocytes from 17 of 18 unique healthy volunteers resulted in downregulated monocyte cell surface expression of HLA-DR by 49.7% ± 22.1%, a phenotype known to mediate both local and systemic immune suppression. Most importantly, monocytes had a positive effect on H23 survival under stress conditions. H23 continuously exposed to cisplatin in culture had improved survival when co-cultured with monocytes for 2 days prior to cisplatin exposure. After 6 days of low serum growth conditions, H23 survival and proliferation was bolstered by the presence of monocytes in culture resulting in a 2 fold greater number of viable H23 cells compared to H23 cultured in low serum without monocytes. These experiments have been repeated and showed that 3 of 4 additional human lung cancer cell lines demonstrated improved survival in low serum growth conditions when co-cultured with monocytes. In conclusion, we have demonstrated the active recruitment of monocytes by lung cancer cell lines, the transformation of the monocytes to an immune suppressive phenotype and the monocyte cancer cross-talk that results in improved tumor survival when exposed to the likely in vivo conditions of a nutrient poor environment or chemotherapy. Taken together these results suggest that the recruitment of monocytes may confer additional survival benefit in the tumor microenvironment beyond local immune suppression and angiogenesis.
Citation Format: Erin Schenk, Allan Dietz. CD14+ monocyte recruitment, transformation and support of tumor survival in a lung cancer model. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A123.