bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A42: CD8+PD-1+ cells population were associated with the superiority of DC/CIK cell immunotherapy combined S-1 in patients with advanced pancreatic and gastric cancer
Authors: Ren Jun , Qiao Guoliang , Wang Xiaoli , Zhou Xinna , Huang Lefu 
Published: February 2019

Abstract
Purpose: Advanced pancreatic(APC) and gastric cancer(AGC) remain challenging to treat effectively. This study aims to investigate the potential role of CD8+PD-1+ T-cells population on the superiority of immunotherapy with dendritic cells and cytokine induced killer cells (DC-CIK) administered with the chemotherapy(S-1).
Methods: Consecutive patients with advanced pancreatic cancer (n=36) and gastric cancer (n=30) were treated with either DC-CIK or DC-CIK+S-1. CIK cells were expanded with IL-2. Flow cytometry and ELISPOT were used for sorting and testing the reactivity CD8+PD-1+ T-cells. Survival estimates were calculated according to the Kaplan and Meier methodology.
Results: The median overall survival(OS) and progression free survival(PFS) for DC-CIK plus S-1 were 212 and 136 days which were significantly higher than other groups for treatment of APC(P&lt;0.001). Similarly, significant differences in PFS and OS were showed in DC-CIK plus S-1 for treatment of AGC(P&lt;0.001). PD-1- and PD-1+ DC-CIK cells were cocultured with their autologous tumor cell lines, and reactivity was assessed by measuring IFN-γ secretion. We found a clear correlation between the percentage of CD8+PD-1+ T-cells on day 7 of culture and the reactivity of the DC-CIKs after 14 days in culture with IL-2. Moreover, CD8+PD-1+ T-cells showed higher tumor specific IFN-γrelease in ELISPOT, compared to CD8+ PD-1- sorted T-cells or unsorted. Further survival analysis showed that patients with the percentage of CD8+PD-1+ T-cells population enhanced more than 2 times after culture had favorable OS and PFS compared with those having no CD8+PD-1+ T-cells increasing. These results showed that CD8+PD-1+ T-cells population might be an excellent biomarker for tumor or antigen-specific activation of adoptive cell therapy.
Conclusion: CD8+PD-1+ T-cells populations were associated with the superiority of DC/CIK combined S-1 and could be a useful biomarker for enriching tumor specific T-cells for cell immunotherapy of patients with APC and AGC.
Citation Format: Jun Ren, Guoliang Qiao, Xiaoli Wang, Xinna Zhou, Lefu Huang. CD8+PD-1+ cells population were associated with the superiority of DC/CIK cell immunotherapy combined S-1 in patients with advanced pancreatic and gastric cancer [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 A42.
Abstract A62: NKG2D RNA CAR is effective in treating peritoneal carcinomatosis in a mouse model
Authors: Li Zhendong , Zha Shijun , Wang Shu 
Published: February 2019

Abstract
Peritoneal carcinomatosis (PC) is widely shown in end-stage neoplastic disease, especially in recurrent colorectal cancer, and has become a significant threat to the overall survival of patients. Since NKG2D ligands are commonly up-regulated on cell surface of carcinomas but rarely present on most healthy tissues, they can be the ideal targets in the treatment of NKG2D ligand-overexpressing colorectal PC. In this study, we developed a chimeric antigen receptor (CAR)-T cell therapy approach by arming human T lymphocytes with mRNA coding a chimeric NKG2D receptor to target NKG2D ligands. We constructed first, second, and third generation CARs specific for NKG2D ligands by linking the extracellular domain of the human NKG2D receptor to the CD3-zeta signaling domain and costimulatory moieties. mRNAs of those chimeric NKG2D CARs were electroporated into human T lymphocytes and the anti-tumor activities of engineered T cells were examined afterwards. The NKG2D CAR expression was detectable for at least 6 days and the modified T cells exhibited efficient cytotoxic immune activity against NKG2D ligand-positive tumor cells, but not NKG2D ligand-negative cells. Multiple infusions of the RNA CAR modified T cells in immunodeficient mice bearing established peritoneal human colorectal tumors led to a significant reduction in the tumor burden. Here, we showed that T cells engineered with NKG2D CAR by RNA electroporation can efficiently control the colorectal peritoneal carcinomatosis in the mouse model. Transfection of mRNA encoding a CAR is an economical way to benefit the test of new CARs and it holds great promise in controlling on-target/off-tumor toxicity and cytokine storms. The possibility of using NKG2D ligand-specific RNA CARs to treat colorectal PC warrants further investigation.
Citation Format: Zhendong Li, Shijun Zha, Shu Wang. NKG2D RNA CAR is effective in treating peritoneal carcinomatosis in a mouse model [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 A62.
Abstract A66: Analysis of dendritic cell derived exosomes that suppressed tumor growth
Authors: Takanashi Masakatsu , Sudo Katsuko , Ueda Shinobu , Ohno Shinichiro , Kuroda Masahiko 
Published: February 2019

Abstract
Immunotherapy is expected as the fourth cancer therapy subsequently to the three pillars of cancer treatment which are surgery, radiation, and chemotherapy. Cancer immunotherapy enhances existing antitumor responses and includes the use of antibodies, lymphocytes and cytokines. Dendritic cells (DCs)-based immunotherapy is one of the cancer immunotherapies. Because DCs play a key role for immune reactions to activate T cells against cancer cells by cancer antigen presentation at cellular membrane, DCs have been used in clinical trials as cellular mediators for therapeutic vaccination of patients with cancer. The cells such as DCs and cancer cells secrete exosomes which are nano-sized extracellular microvesicles. It has reported that the exosomes released from peptide-vaccinated DCs are responsible for the persistence of antigen presentation. On the other hands, cancer cells derived exosomes play an immunosuppressive. So, we considered that whether DCs-derived exosomes could induce suppress cancer cells and more effective response of immune system against cancer with control for the cancer cells-derived exosomes. Luciferase gene transfferd-3LL cells (murine lung cancer cell line derived C57BL/6) were injected to C57BL/6J mice by intraperitoneal administration. And then, DCs, DCs-exosomes or 3LL-exosmes were weekly administrated to lung cancer bearing mice. The exosomes derived from DCs decreased lung cancer cell growth, on the other hand, lung cancer derived-exosomes increased in compared with DCs, DCs-exosomes and non-treated. For cancer immunotherapy, DC-exosomes and controlled cancer-exosomes play important roles. Currently, we are going on analyze immunosuppressive molecules possessing cancer cell-derived exosomes, and immune activation molecules in DCs-exosomes.
Citation Format: Masakatsu Takanashi, Katsuko Sudo, Shinobu Ueda, Shinichiro Ohno, Masahiko Kuroda. Analysis of dendritic cell derived exosomes that suppressed tumor growth [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 A66.
Abstract A67: Bi-phasic metabolic responses to in situ macrophage activation
Authors: Kam Yoonseok , Swain Pamela M. , Dranka Brian P. 
Published: February 2019

Abstract
The cellular metabolism of macrophages is an emerging element regulating inflammatory macrophages which are a critical component of tumor microenvironment. The inflammatory macrophage with highly glycolytic phenotype is also known to elevate the glycolytic activity upon pathogenic stimulation such as lipopolysaccharide (LPS). In this study, the dynamic changes in glycolysis were traced in a real-time manner by measuring proton efflux rates (PERs) and oxygen consumption rates (OCR) after an in-situ activation using Seahorse XFe96 analyzer. The PER of human peripheral blood monocyte (PBMC) derived M1 macrophages was increased within an hour after injection of LPS, which corresponding to cytokine release, tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). In contrast to PBMC-derived M1 macrophage activation, macrophage cell lines of RAW264.7 and J774.A1 required co-stimulation with interferon γ (IFNγ) for the full activation. Interestingly, the LPS and IFNγ co-stimulation modulates glycolytic rates in a bi-phasic manner which was identified only in long term (&gt; 6 hr) monitoring. A series of long term XF analysis using in situ activation revealed that the immediate early glycolytic response fully relies on LPS stimulation while the secondary elevation in PER depends on IFNγ stimulus, which turns on inducible nitric oxide synthase (iNOS) signaling and in turn suppresses mitochondrial respiration. The TNFα production is closely related to the immediate early glycolytic elevation, but independent from IFNγ-induced second elevation. The IFNγ-dependent second glycolysis increase was totally abolished by iNOS inhibitors whereas the immediate early glycolysis elevation was not affected at all. These data imply a temporal orchestration mechanism of LPS and IFNγ signaling in the metabolic regulation and activation of inflammatory macrophages.
Citation Format: Yoonseok Kam, Pamela M. Swain, Brian P. Dranka. Bi-phasic metabolic responses to in situ macrophage activation [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 A67.
Abstract B02: Targeting CSK kinase activity to enhance antitumor immunity
Authors: Wang Cindy , Cao Carolyn , Berman-Booty Lisa , Eraslan Ruki , Sanjuan Miguel , Vite Gregory , Hunt Jack , Fink Brian , Wee Susan 
Published: February 2019

Abstract
To mount an effective tumor immune response, a T cell receptor (TCR) must first recognize a cognate antigen presented by the malignant cells. This antigen-TCR engagement at the cell surface initiates an intracellular signaling cascade that leads to the upregulation of pro-inflammatory and cytolytic cytokines. Successful effector T cell activation in turn results in the elimination of antigen-presenting diseased cells. A key regulator of this signaling cascade is the C-terminal Src (CSK) kinase. In lymphocytes CSK inhibits T cell activation by phosphorylating the SRC kinase family member LCK at tyrosine 505 and thereby terminates the signaling cascade. To assess whether relieving an intracellular blockade of TCR signaling will lead to a more robust T cell response, and hence improved tumor immunity, we developed both genetic and pharmacologic approaches to inhibit CSK activity. A tamoxifen-inducible transgenic CSK knock-out mice was engineered to bypass the embryonic lethality observed with constitutive systemic CSK depletion. As expected loss of CSK enhanced cytokine production and increased anti-tumor immune response in the MC38 syngeneic tumor mouse model. Potent and selective CSK small molecule inhibitors, in the presence of TCR stimulation, similarly activated the proximal TCR signaling pathway and increased cytokine production and proliferation. In an in vivo efficacy study, however, the CSK inhibitor as monotherapy or in combination with aPD1 did not improve anti-tumor immune response at the dose levels tested. This seemingly discrepant finding in tumor response observed in the tamoxifen-inducible KO mice and mice treated with the CSK inhibitor may reflect the need for further optimization in target coverage and dosing regimen. In this poster, we will present our findings on the role of CSK inhibition in tumor immunity.
Citation Format: Cindy Wang, Carolyn Cao, Lisa Berman-Booty, Ruki Eraslan, Miguel Sanjuan, Gregory Vite, Jack Hunt, Brian Fink, Susan Wee. Targeting CSK kinase activity to enhance antitumor immunity [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 B02.
Abstract B09: TLR1/2 ligand promotes Fc gamma RIV mediated depletion of tumor-infiltrating treg by anti-CTLA-4 antibody and its anti-tumor efficacy
Authors: Sharma Naveen , Allison James P. 
Published: February 2019

Abstract
Many cancer patients either do not respond or become resistant to immunotherapy with checkpoint inhibitors. To determine whether activating both the innate and adaptive immune pathways improve the tumor reduction and survival outcomes achieved with immunotherapy, we treated a mouse model of melanoma with intratumoral injections of TLR1/2 ligand plus intraperitoneal injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively, and its efficacy depended on CD4 T cells, CD8 T cells, Fc gamma receptor IV and macrophages. Interestingly, our results suggest a unique and novel mechanism by which TLR1/2 ligand enhances the anti-tumor efficacy of anti-CTLA-4 antibody by increasing Fc gamma receptor IV expression on macrophages and increasing the density of these macrophages in tumor, which in turn enhances the depletion of tumor-infiltrating regulatory T cells. This mechanism could be harnessed to modulate the clinical outcome of other antibody-based immunotherapies.
Citation Format: Naveen Sharma, James P. Allison. TLR1/2 ligand promotes Fc gamma RIV mediated depletion of tumor-infiltrating treg by anti-CTLA-4 antibody and its anti-tumor efficacy [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 B09.
Abstract B13: New drug repositioning of low-dose pegylated IFN-alpha in combination with BH3 interacting domain death agonist gene and radiation therapy as a cancer treatment regimen
Authors: Tsuno Takaya , Kanno Shohei , Ryoichi Iwata , Tanigawa Noboru , Ueba Tetsuya 
Published: February 2019

Abstract
Purpose: Chemotherapy and radiation therapy (RT) are frequently selected for cancer treatment regimens, however they have limitations. Further regimens should be considered to overcome difficulties in cancer treatments. We have reported that interferon (IFN)-alpha induces in vitro cell death mediated by BH3-interacting domain death agonist (BID). However, low-dose pegyrated (PEG)-IFN-alpha, which suggests the possibilities of better adherence and fewer side effects, is clinically approved for treatment of hepatitis C, but not for that of any tumors. RT may also induce cell death. Here we assessed in vivo antitumor effects of pIRES-hBID (BID) transfection followed by low-dose PEG-IFN-alpha and RT (BID+IFN+RT).
Experimental Procedures: A549 human lung carcinoma cells are resistant to both IFN-alpha and RT. In the present study, BID and low-dose PEG-IFN-alpha were administered into nude mice bearing subcutaneous A549 xenografts. The mice were then irradiated with 3 Gy gamma ray. These treatments were performed once a week for 4 weeks.
Results: No body weight-loss was observed following any treatments. Immunohistochemistry demonstrated significantly less intranuclear localization of BID protein induced by BID alone and BID+IFN compared to mock alone and BID alone, respectively. These results suggest that each of BID and low-dose PEG-IFN-alpha affected BID translocation. Assessment of tumor volume indicated synergistic effects of growth inhibition induced by BID+IFN+RT. Electron microscopic examination of tumors on Day 56 demonstrated not only fragmented plasma membranes and nuclei but also cytoplasmic vesicles with degraded contents induced by BID+IFN+RT, indicating that low-dose PEG-IFN-alpha and RT following BID may induce both apoptotic and non-apoptotic cell death including autophagy and/or necrosis.
Conclusions: Even low-dose PEG-IFN-alpha likely had antitumor effects when combined with BID and RT, suggesting the possibility of new drug repositioning of PEG-IFN-alpha. Consequently, BID+IFN+RT may be a promising regimen for treating tumors that are resistant to both IFN-alpha and RT.
Citation Format: Takaya Tsuno, Shohei Kanno, Iwata Ryoichi, Noboru Tanigawa, Tetsuya Ueba. New drug repositioning of low-dose pegylated IFN-alpha in combination with BH3 interacting domain death agonist gene and radiation therapy as a cancer treatment regimen [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 B13.
Abstract B33: Coexpression and frequency of immune checkpoint proteins in the tumor microenvironment analyzed via multiplex immunohistochemistry
Authors: Ziello Jennifer , Klein Sarah , Crosby Katherine 
Published: February 2019

Abstract
Antibody blockade of the PD-1/PD-L1 axis is approved for clinical use in multiple tumor types in an effort to block tumor immune evasion. The high number of emerging cancer immunotherapy agents indicates that there is an increased importance in assessing and understanding the immunosuppressive tumor microenvironment. In this study, we applied a 7-color multiplex immunohistochemistry panel to a lung tumor tissue microarray consisting of FFPE adenocarcinoma and squamous cell carcinoma cores. The panel was composed of immune checkpoint receptors PD-1 and TIM-3; PD-L1, a PD-1 ligand; CD68 and CD8, macrophage and cytotoxic T cell markers, respectively; as well as cytokeratin as the tumor mask and DAPI as the nuclear counterstain. The array included three cores per patient, and the concordance between fields was analyzed. Additionally, the frequency and co-localization of these markers and checkpoint proteins in the tumor and tumor microenvironment were quantified. TIM-3 expression was found not only on CD8+ T cells, but also on CD68+ macrophages, where it is thought to have a distinct function involved in phagocytosis of tumor cells. Furthermore, the significant role that macrophages play in tumor progression via promoting angiogenesis and inhibiting antitumor immunity makes these data increasingly relevant. These data demonstrate how antibody-based multiplex analysis in tissue can provide insight into the various cell types involved in tumor-mediated immune evasion. Multiplex IHC with highly specific antibodies will serve to improve our understanding of how immunotherapies can be used to affect the innate and adaptive branches of the immune system in the course of cancer treatment.
Citation Format: Jennifer Ziello, Sarah Klein, Katherine Crosby. Coexpression and frequency of immune checkpoint proteins in the tumor microenvironment analyzed via multiplex immunohistochemistry [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 B33.
Abstract B41: Neutrophils modulate T-cell recruitment and promote hepatic metastases in lung cancer
Authors: Rayes Roni F. , Tinfow Alexandra , Antonatos Dorothy , Bourdeau France , Giannias Betty , Spicer Jonathan D. 
Published: February 2019

Abstract
Immunotherapy using checkpoint inhibitors has shown success in the treatment of late-stage non-small cell lung carcinomas (NSCLC). Indeed, nivolumab (anti-PD1 antibody) increased overall response by 9 % and overall survival by 3 months compared to chemotherapy (docetaxel). Combining Ipilimumab (anti-CTLA-4 antibody), another immune checkpoint inhibitor, with nivolumab was shown to improve response rates and survivals in NSCLC patients compared to nivolumab alone (phase 1/2 study). Despite these advances, there are still many patients that are non-responsive to available immunotherapies. We hypothesize that the immune system can overtake the inhibition of immune suppression via other mechanisms leading to a more immune suppressive tumor microenvironment. Neutrophils, being amongst the first cells of our innate immune system to be recruited to the tumor microenvironment, are key players in modulating other immune cells. Indeed, we and others have demonstrated that neutrophils play a critical role during cancer progression and from a clinical standpoint elevated neutrophil counts both in circulation and within growing lesions have been associated with poor oncologic outcomes. Therefore, neutrophil could well be the immunosuppressive switch in the tumor microenvironment. To test our hypothesis, we injected liver metastatic lung carcinoma cells into mice treated with daily injection of neutrophil elastase inhibitor (NEi, Sivelestat) and into untreated (control) mice. We then collected the livers of those mice at multiple time points post-tumor inoculation and analyzed the immune profile of these mice. As expected, NEi-treated mice had significantly less liver metastases than control mice (p &lt; 0.05) indicating that neutrophils play a pro-tumor role in cancer progression. Furthermore, NEi-treated mice had a significant decrease in the number of tumor infiltrating granulocytes (GR1+ cells, p &lt;0.05) and tumor associated neutrophils (TANs, Ly6G-1A8 + cells) (p&lt;0.0005). This significant decrease in TANs correlated with a significant decrease in CD3+ T-cells (p&lt;0.05) in NEi-treated mice compared to control mice 1-week post-tumor injection. The number of tumor associated macrophages (F4/80+ cells) was the same in both groups (p=0.65) and thus not affected by the significant decrease in TANs. These findings show that neutrophils play a role in T-cell recruitment in liver metastases of lung cancer cells and thus neutrophil can be an important target for new immunotherapies.
Citation Format: Roni F. Rayes, Alexandra Tinfow, Dorothy Antonatos, France Bourdeau, Betty Giannias, Jonathan D. Spicer. Neutrophils modulate T-cell recruitment and promote hepatic metastases in lung cancer [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 B41.