bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 758: Cancer vaccine immunotherapy employing Saccharomyces cerevisiae (yeast) as a vector can modulate the balance between CD4+ T cells and regulatory T cells (Tregs) and enhance the specific antitumor immune response
Authors: Vergati Matteo , Cereda Vittore , Intrivici Chiara , Huen Ngar-Yee , Bari Maria Giovanna Di , Jochems Caroline , Gulley James L. , Apelian David , Schlom Jeffrey , Tsang Kwong Y. 
Published: June 2012

Abstract
Regulatory T cells (Tregs) have been broadly related to modulation of the antitumor immune response. We have previously shown that whole, heat-killed, recombinant Saccharomyces cerevisiae yeast genetically modified to express carcinoembryonic antigen (yeast-CEA) can efficiently activate human dendritic cells (DCs) and stimulate CEA-specific CD8+ T cells. In the present study, we further investigated how the balance between CD4+ T cells and Tregs induced by yeast-treated DCs might affect the generation of a CEA-specific immune response. Autologous CD4+ T cells were co-cultured with human DCs matured by yeast vs. CD40L. Activated CD4+CD25+ effector T cells (Teffs) and CD4+CD25+CD127- Tregs isolated from the two co-cultures were analyzed. A higher Teff/Treg ratio, greater levels of Th1-related cytokines, lower expression of FoxP3 in Tregs, decreased FoxP3 demethylation levels in the Treg-specific demethylated region, and decreased Treg suppressive function were found in the cells isolated from the yeast co-culture compared to those from the CD40L co-culture. DCs isolated from the yeast co-culture showed a significant decrease in surface expression of programmed death ligand 2 (PD-L2) vs. the CD40L co-culture (55.7% vs. 31.2%). No differences were observed in programmed death ligand 1 (PD-L1) levels. Teffs isolated from the yeast co-culture had higher levels of PD-L1 (22.9% vs. 13.7%), but significantly lower levels of programmed death 1 (PD-1, 2.4% vs. 11.6%), compared to the co-culture using CD40L-matured DCs. Tregs isolated from the yeast co-culture showed a significant increase in surface expression of PD-L1 (25.5% vs. 3.6%) and no difference in levels of PD-1 (0.7% vs. 1.4%) compared to the CD40L co-culture. These pro-inflammatory changes may partially explain both the increased CEA-specific CD4+ T-cell proliferation using yeast- vs. CD40L-treated DCs pulsed with CEA protein, and the higher percentage of CEA-specific CD4+ T cells generated when yeast-matured DCs vs. CD40L-treated DCs were used as antigen-presenting cells in the presence of CEA protein. This is the first study to report on the role of yeast-treated human DCs in modulating the balance between Teffs and Tregs and thus enhancing the antitumor immune response. Altogether, these preliminary findings provide a rationale for further evaluation of yeast constructs in cancer vaccine immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 758. doi:10.1158/1538-7445.AM2011-758
Abstract 772: Targeted cancer therapy with immunotoxins
Authors: Wiiger Merete T. , Fodstad Øystein , Andersson Yvonne 
Published: June 2012

Abstract
The therapeutic options for patients with metastasis are generally limited and the need to develop better treatment modalities is obvious. Immunotoxins (ITs) represent a promising group of targeted therapeutics, consisingt of a cancer-specific antibody and a cell killing toxin. The number of IT protocols approved for treatment of cancer patients is expected to increase, as this type of treatment has several advantages compared to conventional strategies. Unfortunately, the clinical use of ITs has been hampered by liver toxicity and the induction of a strong anti-IT-antibody response. However, in an ongoing clinical phase I study with one of our ITs, targeting EpCAM, in combination with the immunosuppressor cyclosporin (CsA) we have demonstrated only transient liver toxicity and minimal/no anti-IT antibody response.
We are now investigating the potential use of our-clinical grade BM7PE for patients with triple-negative breast cancer (TNBC) and peritoneal carcinomatosis from ovarian cancer, for whom standard treatment is no longer an option. This IT targets Mucin-1 which is over-expressed and aberrantly glycosylated in these cancer types.
We have found that the combination of BM7PE and CsA caused a remarkable synergistic effect in killing the TNBC cell lines MDAMB468 and MDAMB231, as well as in the ovarian cell line B76, established from pleural effusion. The mechanisms underlying this synergism in vitro have been thoroughly studied in cell viability assays, western blot and PCR-arrays. Preliminary data show reduced Matrigel invasion, which was even more inhibited by the combination with CsA. This suggests that the IT treatment does regulate cellular migration and invasion. Further investigations are ongoing to identify molecular pathways involved in IT- (+/-CsA) induced cell death and invasion.
In conclusion, the combination of BM7PE and CsA might constitute an important improvement and increase the possible clinical potential of IT in these patient groups.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 772. doi:10.1158/1538-7445.AM2011-772
Abstract 775: Sequential common gamma-chain cytokines facilitate differentiation of tumor-reactive T cells that are resistant to MDSC and can induce rejection of breast tumors
Authors: Payne Kyle K. , Kmieciak Maciej , Basu Debasmita , Ramakrishnan Viswanathan , Bear Harry D. , Manjili Masoud H. 
Published: June 2012

Abstract
Adoptive T cell immunotherapy (AIT) utilizing ex vivo expanded HER-2/neu-specific T cells is a promising modality in the treatment of patients with breast carcinoma. Previously, our group has described the ability of tumor-sensitized T cells activated ex vivo with bryostatin 1 and ionomycin (B/I) and subsequently expanded with common γ-chain receptor family cytokines IL-2 and IL-7/IL-15 cultured in an alternating manner to induce primary breast tumor regression in FVBN202 transgenic mice. These results, however, required the combination of AIT with in vivo depletion of myeloid-derived suppressor cells (MDSCs) as the presence of these cells abrogated the anti-tumor efficacy of neu-specific lymphocytes. Presently, we report the implementation of a novel ex vivo expansion protocol, in which IL-2 and IL-7/IL-15 are cultured in a sequential manner post B/I with tumor-specific activated cells and support expansion of tumor reactive CD44+CD62L− effector T cells (TE) and CD44+CD62L+ central memory T cells (TCM). We show that tumor-specific cells activated in this manner induce rejection of primary breast tumor and provide long-term protection against the tumor, even in the presence of MDSC. Of particular interest, tumor-reactive CD4+ and CD8+ lymphocytes expanded with this method conferred resistance to the suppressive effects of MDSCs in vitro. Additionally, we demonstrate that innate immune cells are essential in eliciting tumor rejection. Flow cytometric analysis indicates Natural Killer (NK) and Natural Killer T-cell (NKT) as well as the Interferon-γ Producing Killer Dendritic Cell (IKDC) populations significantly increase following ex vivo expansion with sequential common γ-chain cytokines. Depletion of innate immune cells in adoptively transferred cells resulted in the failure of AIT to reject tumor. Together, our data suggest that sequential common γ-chain cytokines can support differentiation of tumor-reactive T cells which are resistant to MDSC, as well as innate immune cells which may be essential in supporting the anti-tumor efficacy of T cells. These results potentially provide a new paradigm in therapeutic AIT of breast carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2011-775
Abstract 785: The progesterone induced blocking factor, an immunomodulatory protein that may suppress natural killer cell activity in the tumor microenvironment, found to be a soluble protein possibly allowing the development of an enzyme-linked immunoabsorbent assay
Authors: Cohen Rachael , Srivastava Maya , Check Jerome H. , Dix Ebony 
Published: June 2012

Abstract
A unique 34 kDa protein expressed by gamma delta thymic (T) cells during pregnancy suppresses natural killer (NK) cell activity and helps to shift the balance of thymic helper (TH) 1 to TH2 cytokine dominance. The mechanism involved in making this immunomodulaotry protein involves de novo induction of progesterone (P) receptors on gamma delta T cells by the allogeneic stimulus of the fetal semi-allograft and the interaction of the P receptors with a high concentration of P generated at the maternal fetal interface. There is evidence that certain cancer cells may use a similar mechanism to escape NK cell surveillance as evidenced by all 27 different human leukemia cells tested showing a very high level of messenger RNA for this immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Furthermore adding the P receptor antagonist mifepristone down-regulated PIBF expression. PIBF may be synthesized by gamma delta T cells in the tumor microenvironment of solid tumors thus inhibiting NK cell immunosurveillance. Previous studies were performed using an immunocytochemistry technique using a polyclonal antibody because the PIBF protein was not purified. Recombinant DNA technology has allowed the production of a pure protein and thus the development of a monoclonal antibody. The present study was aimed at determining if PIBF is a soluble protein, which if it is could lead to the development of a much more practical and sensitive enzyme linked immunoabsorbent assay (ELISA). Serum samples were blindly assessed for the presence of PIBF using a novel sandwich ELISA we developed with full length (amino acid 1 to 757) recombinant human PIBF, rabbit polyclonal antibody to amino acid 1-300, and affinity purified goat polyclonal antibody to the internal region of PIBF conjugated to horseradish peroxidase. Color was developed using tetramethylbenzidine substrate stopped by 2N H2SO4 and read at 450 lambda. Bovine serum albumin served as negative control. Soluble PIBF was detected in several samples, with highest levels in pregnant patients at over 10 microgram/ml concentration. There were significant inter-individual differences. PIBF, does indeed also exist in a soluble form and can be detected in serum. With further refinement of our ELISA we aim to improve sensitivity and specificity, allowing for the simple measurement of PIBF on a rapid, high throughput basis, making it a more practical test to predict cancers that would benefit from progesterone receptor antagonist therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 785. doi:10.1158/1538-7445.AM2011-785
Abstract 791: T cells in visceral adipose tissue: A potential source of inflammation to drive tumorigenesis
Authors: Lysaght Joanne , Allott Emma H. , Donohoe Claire L. , Howard Julia M. , Pidgeon Graham P. , Reynolds John V. 
Published: June 2012

Abstract
Introduction: Visceral adipose tissue is believed to be fuelling a state of chronic inflammation in obese patients, establishing an environment favourable for tumor growth. However, the exact immunological mechanisms remain unclear. Recent animal studies have pointed to an important role for visceral adipose tissue CD8+ T cells in both the establishment of and maintenance of adipose tissue inflammation in obese models. This novel study aimed to phenotypically characterize both CD4+ and CD8+ T cells in the omentum of esophageal adenocarcinoma (EAC) patients, as EAC has one of the strongest association with obesity and arises in a background of inflammation.
Methods: Peripheral blood and visceral adipose tissue from the greater omentum were taken from 30 EAC patients at the commencement of resectional surgery. Peripheral blood mononuclear cells were isolated using density centrifugation and the stromal vascular fraction of the adipose tissue was obtained following collagenase digestion. T cell activation status and cytokine production were assessed by both surface and intracellular flow cytometry and serum cytokines were determined by ELISA.
Results: The omentum was found to be a rich source of both CD4+ and CD8+ T cells, which display an activated inflammatory phenotype, expressing significantly higher (p&lt;0.0001) CD69, CD107a, CD45RO and IFN-γ than T cells in the blood. Omental CD8+ T cells also expressed significantly higher (p&lt;0.0001) IFN-γ than CD4+ T cells, suggesting that CD8+ T cells are an important source of this inflammatory cytokine within visceral fat. The highest circulating levels of the IFN-γ were detected in the serum of viscerally obese cancer patients.
Conclusions: This novel study demonstrates that omental T cells may be key players in driving adipose tissue inflammation, potentially mediated by IFN-γ. The highest serum levels of IFN-γ were detected in viscerally obese cancer patients, suggesting that visceral adipose tissue may be the source of this inflammatory cytokine, thus providing an immunotherapeutic target to attenuate chronic inflammation associated with visceral obesity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 791. doi:10.1158/1538-7445.AM2011-791
Abstract 793: Direct inhibitory effects of gastric cancer against dendritic cells
Authors: Iwauchi Takehiko , Tanaka Hiroaki , Yoshii Mami , Ito Gentaro , Kimura Kenjiro , Nagahara Hisashi , Noda Eiji , Amano Ryosuke , Kubo Naoshi , Muguruma Kazuya , Yamada Nobuya , Yashiro Masakazu , Maeda Kiyoshi , Ohira Masaichi , Hirakawa Kosei 
Published: June 2012

Abstract
Dendritic cells (DC) are professional antigen-presenting cells which englobe tumor-associated antigens and activated cytotoxic T lymphocytes. Otherwise, in recent studies, it has been demonstrated that immature DC such as tolerogenic DC were associated with suppression of anti-tumor immune response. The immature DC infiltrating tumor microenvironment promote tumor growth and angiogenesis in lung cancer, ovarian cancer and breast cancer. Various cytokines secreted by pancreatic cancer suppress the maturation of DC. CD4+CD25+ regulatory T cells inhibit the anti-tumor response against colon cancer. Although it has been suggested that regulatory T cells and tolerogenic DC might be associated with the immunosuppressive mechanism in cancer patients, it has not been revealed yet. In this study, we examined direct inhibitory effects of gastric cancer against DC. We designed to assess the effects of tumor-associated cytokines secreted by gastric cancer cells on DC maturation and function. Next, after culturing DC in the medium with supernatant of gastric cancer and protein-bound polysaccharide K (PSK), we examined cytokines of interleukin-10 (IL-10) of DC, which considered immunosuppressive cytokine. Various gastric cancer cell lines, included scirrhous gastric cancer secreted immunosuppressive cytokines, such as TGF-β, IL-10 and VEGF. The expression of HLA-DR as positive costimulatory molecule of DC was decreased, and that of programmed death-ligand 2 (PD-L2), as negative costimulatory molecule was increased in the medium included supernatant of gastric cancer cells. IL-10 secreted in the supernatant of DC cultured with supernatant of gastric cancer cells was increased, and inhibited by co-culturing with PSK. In conclusion, the maturation of DC was inhibited by various immunosuppressive cytokines secreted by gastric cancer cells and tolerogenic DC were induced. These results suggest that tolerogenic DC infiltrates around tumors, inhibits immune response against tumors and promote growth of tumor in gastric cancer patients. In addition, PSK might suppress the effects of tolerogenic DC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 793. doi:10.1158/1538-7445.AM2011-793
Abstract 796: Impact of histological types on infiltration of regulatory T cells in gastric cancer
Authors: Yoshii Mami , Tanaka Hiroaki , Sakurai Katsunobu , Nagahara Hisashi , Kimura Kenjirou , Amano Ryousuke , Noda Eiji , Kubo Naoshi , Muguruma Kazuya , Yamada Nobuya , Yashiro Masakazu , Maeda Kiyoshi , Sawada Tetsuji , Ohira Masaichi , Ishikawa Tetsurou , Hirakawa Kosei 
Published: June 2012

Abstract
Introduction: It is recently known that regulatory T cells (Tregs) are naturally present in the immune system and play important roles of suppression in host's antitumoural immune response. The transcription factor forkhead box P3 (FoxP3) is the most reliable marker for Tregs, and involved in the development and function of Tregs. Previous studies have pointed out that increasing of Tregs were associated with progression of many solid cancers such as breast cancer, melanoma, head and neck cancer, esophageal cancer. However, few reports were found about gastric cancer. Signet ring cell carcinoma with more advanced stage increase the risk of metastasis, like scirrhous carcinoma. It is uuclear whether the number of Tregs is correlated with the progression of signet ring cell carcinoma. The aim of this study is to investigate the population of tumor infiltrating Tregs and the impact of histological types on that in gastric cancer.
Materials and methods: A total of 100 patients with gastric cancer who underwent gastrectomy between 2003 and 2008 at our institute were enrolled. FoxP3 expression in primary gastric cancer was analyzed by immunohistochemistry. T cells expressed FoxP3 were defined as Tregs.
Results: Our cohort of 100 patitents included almost all histological types of gastric cancer, including tubular adenocarcinoma, poorly differentiated adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, squamous cell carcinoma, and signet ring cell carcinoma. We detected FoxP3 expression in more than 90% of primary tumors. FoxP3 positive cells infiltrating into tumor were considered as Tregs. The localization of observed infiltrating Tregs expanded to not only tumor but also regional lymph node. The number of Tregs in tumor increased according to the differentiation of the cancer cells. Importantly, we detected significant few tumor infiltrating Tregs in signet ring cell carcinoma compared with the other histological types. On the other hand, signet ring cells themselves expressed FoxP3, indicating that signet ring cells might play a role of suppression of immune response to cancer.
Conclusion: We have observed that there were differences between signet ring cell carcinoma and other histological types with regard to the distribution of FoxP3 expression cells. Although the detail clinical investigation is needed, our result suggested that taylor made arrangement associated with histological types should be required for immunotherapy against gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2011-796
Abstract 801: Uptake of exogenous neutrophil elastase by breast cancer cells: A novel link between innate immunity, inflammation and breast cancer immunity
Authors: Mittendorf Elizabeth A. , Alatrash Gheath , Qiao Na , Xiao Haile , Sukhumalchandra Pariya , Quintanilla Kathryn , Clise-Dwyer Karen , Molldrem Jeffrey 
Published: June 2012

Abstract
Introduction: High level of neutrophil elastase (NE) in tumor tissue from breast cancer (BrCa) patients is associated with poor metastasis-free survival. Modest endogenous expression of NE in some BrCa cell lines has also been observed. However, because the major source of NE is from azurophil granules of activated neutrophils, we hypothesized that breast cancer cells may take up soluble NE released by abundant inflammatory cells in the tumor microenvironment.
Methods: Endogenous NE expression was evaluated in MCF7, HER18, MDA-MB-231 (231) and MDA-MB-453 BrCa cell lines by western blot analysis and RT-PCR. Uptake of soluble NE was quantified by flow cytometry by intracellular staining of NE-pulsed BrCa and compared to non-specific uptake of OVA. Dose and time course experiments were performed. Confocal immunoflourescence microscopy was used to confirm uptake and demonstrate subcellular localization of NE. BrCa cells were also co-incubated with activated neutrophils to determine if they were able to take up cell-associated NE.
Results: Western blot analysis of BrCa cell lysates showed no NE protein expression in all 4 cell lines. Furthermore, RT-PCR with NE-specific primers demonstrated no NE mRNA expression in the 4 BrCa cell lines. However, BrCa cells pulsed with 5 to 25 μg/ml of soluble NE took up NE in a time and dose dependent manner, consistent with a receptor-mediated mechanism. Maximal intracellular uptake of NE by 231 cells occurred by 24 hours when NE accumulated at comparable levels to that of HL60 leukemia cells that express high levels of NE (987 vs 1300 MFI, p=ns). Uptake was enzyme-independent because it was not affected by alpha-1-antitrypsin, a protease inhibitor. Confocal microscopy demonstrated that NE accumulates in membrane bound compartments by 20 minutes after uptake, whereas there was no significant uptake of OVA by BrCa cells. Similarly, after co-incubation of 231 cells with activated neutrophils, significant uptake of NE was detected (p&lt;.001).
Conclusions: These data show that BrCa cells do not express NE but the cells take up extracellular NE by a receptor-mediated enzyme-independent mechanism. This establishes a novel link between NE, a naturally secreted mediator of inflammation and cell growth, and BrCa. Because neutrophils are the major source of NE and chronic inflammation by tumor-infiltrating neutrophils is associated with positive tumor growth, this suggests NE could mediate growth control of BrCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 801. doi:10.1158/1538-7445.AM2011-801