bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1274: Hallmark of immune responses to multiple tumor-associated antigens (TAAs) in immunodiagnosis of hepatocellular carcinoma (HCC) and other solid tumors
Authors: Dai Liping , Li Pei , Liu Weihong , Luo Chenglin , Tan Eng M. , Zhang Jianying 
Published: August 2015

Abstract
The immune system of the patient with cancer is a sensitive sensor of alterations in structure and/or function of participants in tumorigenesis pathways and is capable of making immune responses in the form of autoantibodies to tumor-associated antigens (TAAs). A hallmark of this immune response is the production of autoantibodies of multiple specificities indicating the activation of more than one tumorigenesis pathway. Novel autoantibodies appear prior to or coincident with clinical detection of transformation to cancer. Activation of more than one tumorigenesis pathway expressed as multiple autoantibodies to TAAs is a finding consistent with the synthetic lethality paradigm where mutation of more than one gene or in the case of cancer, more than one tumorigenesis pathway is required for malignant transformation. After analyzing 321 sera from patients with different type of cancer for autoantibodies to seven selected TAAs including p53, c-myc, cyclin B1, p62, KOC, IMP1 and Survivin, 34% of the sera had autoantibody to one TAA and 20% had two to six autoantibodies simultaneously. In a recent study, we have used a mini-array of 14 selected TAAs as an approach in the immunodiagnosis of HCC, and found that 68% of the sera contained one or more than one antibodies against these TAAs. In addition, this TAA array can identify 43.8% of HCC patients who had normal AFP levels in serum. Some autoantibodies appeared de-novo concurrent with conversion to malignancy. Many novel target antigens besides the above have been identified and shown to be participants in tumorigenesis. The immune system response to TAAs is a repository of information on partners in the synthetic lethality paradigm. Our study can also support the hypothesis that a customized TAA array used for detecting anti-TAA autoantibodies can constitute a promising and powerful tool for immunodiagnosis of HCC and other solid tumors.
Citation Format: Liping Dai, Pei Li, Weihong Liu, Chenglin Luo, Eng M. Tan, Jianying Zhang. Hallmark of immune responses to multiple tumor-associated antigens (TAAs) in immunodiagnosis of hepatocellular carcinoma (HCC) and other solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1274. doi:10.1158/1538-7445.AM2015-1274
Abstract 1280: Clinical features of transcriptional factor Helios expression on regulatory T cells in patients with non-small cell lung cancer
Authors: Muto Satoshi , Owada Yuki , Inoue Takuya , Watanabe Yuzuru , Yamaura Takumi , Fukuhara Mitsuro , Okabe Naoyuki , Matsumura Yuki , Hasegawa Takeo , Osugi Jun , Hoshino Mika , Higuchi Mitsunori , Suzuki Hiroyuki , Gotoh Mitsukazu 
Published: August 2015

Abstract
Introduction
Foxp3+ regulatory T cells (Tregs) have been thought to have at least two subsets: natural Tregs (nTregs) and induced Tregs (iTregs). Recently, expression of the transcription factor Helios, a member of the Ikaros gene family, has been expected to be a molecular marker of nTregs, but this is still controversial. To date, several in vitro studies and animal model studies regarding Helios have been reported, but there has been no examination of the clinical impact of Helios expression on Tregs in patients with lung cancer to date.
Methods
A total of 45 non-small cell lung cancer (NSCLC) patients who underwent surgical resection and 19 advanced/recurrent NSCLC patients was evaluated. Peripheral blood mononuclear cells (PBMCs) taken from these patients were examined by flow-cytometry. Of these 45 patients, 18 who were evaluable for tumor tissue underwent immunohistochemical investigation for tumor-infiltrating lymphocytes.
Results
Helios-negative Tregs of CD4+ T cells were significantly higher not only in all cancer patients (2.4%), but also in stage IA patients (2.6%) as compared with normal controls (1.5%, p&lt;0.001). Patients who had a lower level of Helios-negative Tregs in tumor-infiltrating lymphocytes had significantly longer survival (p = 0.038).
Discussion
Helios-negative Tregs may be involved in immune suppression, even in early-stage NSCLC. The frequency of Helios-negative Tregs could be a useful prognostic biomarker in patients with NSCLC. The biological functions of Helios-negative Tregs in immune suppression should be further examined.
Baseline demographicsCharacteristicN (%)Age (y)Mean±SD67±8SexFemale27 (42)Male37 (58)Pathological stageIA22 (34)IB16 (25)IIA4 (6)IIB3 (5)III0 (0)IV (Recurrence included)Chemotherapy1st-line6 (9)2nd-line6 (9)3rd or later-line7 (11)Pathological classificationAdenocarcinoma51 (80)Squamous cell carcinoma10 (16)Others3 (5)EGFR mutationPositive22 (34)Negative31 (48)Unknown11 (17)
Citation Format: Satoshi Muto, Yuki Owada, Takuya Inoue, Yuzuru Watanabe, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Osugi, Mika Hoshino, Mitsunori Higuchi, Hiroyuki Suzuki, Mitsukazu Gotoh. Clinical features of transcriptional factor Helios expression on regulatory T cells in patients with non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2015-1280
Abstract 1284: Analysis of the immune suppression mechanism in extra-hepatic cholangiocarcinoma
Authors: Wada Satoshi , Tsukagoshi Mariko , Watanabe Akira , Kubo Norio , Araki Kenichiro , Suzuki Hideki , Kuwano Hiroyuki 
Published: August 2015

Abstract
Introduction
Extra-hepatic cholangiocarcinoma (EHCC) has not been improved with the five-year survival rate for more than 10 years, which is a refractory cancer of poor prognosis. Development of novel therapeutic agents has been desired, because the standard chemotherapy has not been established yet. Anti-tumor immunotherapy is expected for less burden on the patient in recent years. However, it is limited by multiple tolerogenic mechanisms related to the tumor, the host immune system, and the tumor microenvironment. Therefore satisfactory results are not obtained in the clinical trials for several vaccinations. In this experiment, we focused on negative co-signaling molecules, especially immune checkpoints. The purpose of the present study was to investigate the relationship between the expression of immune checkpoints and clinico-pathological findings, including prognosis in EHCC patients.
Patients and specimens
We enrolled 81 patients (56 men and 25 women; age range: 36-84 years) with EHCC who underwent curative resection with lymphadenectomy at Gunma University Hospital and Saiseikai Maebashi Hospital (Maebashi, Japan) between 2000 and 2011. Patients who had undergone palliative resection, preoperative chemotherapy and radiation therapy were excluded from this study. Furthermore, none of the patients enrolled in this study had synchronous or metachronous cancer in other organs.
Results
Immunohistochemical staining of immune checkpoints in primary EHCC tissue was performed. Patients with high B7-H4 expression had a significantly poorer prognosis than those with low B7-H4 expression. However, it was not seen in B7-H3 expression in this experiment. Furthermore, in analysis for the expression of CD8, IFN-γ and FOXP3, patients with high FOXP3 expression had a significantly poorer prognosis than those with low FOXP3 expression.
Conclusion
The B7-H4 is a negative co-stimulatory molecule and a novel prognostic marker related to the T-cell mediated immune response. It's pathway may be a molecular target for controlling tumor progression in patients with EHCC.
Citation Format: Satoshi Wada, Mariko Tsukagoshi, Akira Watanabe, Norio Kubo, Kenichiro Araki, Hideki Suzuki, Hiroyuki Kuwano. Analysis of the immune suppression mechanism in extra-hepatic cholangiocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1284. doi:10.1158/1538-7445.AM2015-1284
Abstract 1299: Tumor-infiltrating B cells are predictive of human lung squamous cell survival
Authors: Centuori Sara , Kim Samuel , Gomes Cecil , Putnam Charles , Mount David , Garland Linda , Martinez Jesse 
Published: August 2015

Abstract
Recent studies in human lung squamous cell carcinoma (SqCC) have shown that upregulation of B cell-associated genes strongly correlate with patient survival. More than any genetic factor (immunologic or otherwise) CD79A, a pan-B cell marker, was found to have the strongest predictive value. Expression of this marker was capable of identifying short (&lt; 2 years) and long (&gt; 6 years) term lung SqCC survivors, with greater than 80% accuracy. These data suggest that the presence of CD79A-expressing tumor-infiltrating B (TIL-B) cells may be contributing to patient outcome. The aim of this study was to characterize CD79A+ TIL-B cells in SqCC patient samples and evaluate their role in lung SqCC survival. We evaluated human lung cancer specimens from long and short term survivors for the presence of CD79A+ TIL-B cells by immunofluorescence and found that their presence directly correlates with survival time. Further analysis showed that CD79A expression found in tumors of long term survivors (&gt;6 years) co-localizes with CD20 staining but not CD138 staining, indicating that the cells responsible for producing a survival signature are not plasma cells. These data indicate that CD79A+ TIL-B cells are contributing to the generation of an efficient immune response in lung SqCC and may be doing so through non-humoral functions.
Citation Format: Sara Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Jesse Martinez. Tumor-infiltrating B cells are predictive of human lung squamous cell survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2015-1299
Abstract 1303: Quantification of natural killer cell-mediated cytotoxicity using Celigo imaging cytometry
Authors: Chan Leo Li-Ying , Rosbach Kelsey , Somanchi Srinivas S. , Lee Dean 
Published: August 2015

Abstract
Cytotoxicity assays play a central role in studying the function of immune effector cells such as cytolytic T lymphocytes (CTL) and natural killer (NK) cells. Traditionally, cytotoxicity assays have been performed using 51Chromium (51Cr) and Calcein release assays. The assays involve labeling tumor cells (target) with radioisotope or fluorescent dyes, when the target cells are subjected to cytolysis by CTLs or NK cells (effector), they releases the entrapped labels into the media upon lysis. The amount of labels in the media is measured to determine the level of cytotoxicity the effectors have induced. These traditional methods may generate inconsistent results due to low sensitivity caused by poor loading efficiency and high spontaneous release of the reagents. In this work, we demonstrate a novel cytotoxicity assay using the Celigo imaging cytometry method. Utilizing imaging cytometry, direct cell counting of live fluorescent target cells can be performed, which is a direct method for assessment of cytotoxicity. Human NK cells from one healthy donor were used as effectors, and K562 (suspension) and IMR32 (adherent) were used as the target cells. Both target cells were first stained with Calcein AM, and seeded at 10,000 cells/well in a standard 96-well microplate. The donor NK cells were then added to each well at Effector-to-Target (E:T) ratios 10:1, 5:1, 2.5:1, 1.25:1, 0.625:1, and 0.3125:1. The 96 well plate was then scanned and analyzed using Celigo imaging cytometer at t = 1, 2, 3, and 4 h to measure the% lysis of target cells. The results showed increasing% lysis as incubation time and E:T ratio increased. The propose Celigo imaging cytometry is an accurate and simple method for direct quantification of cytotoxicity.
Citation Format: Leo Li-Ying Chan, Kelsey Rosbach, Srinivas S. Somanchi, Dean Lee. Quantification of natural killer cell-mediated cytotoxicity using Celigo imaging cytometry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1303. doi:10.1158/1538-7445.AM2015-1303
Abstract 1304: Identification of responders for Anti-CTLA4 in refractory colorectal cancers using CANScript™ platform
Authors: Majumder Biswanath , Ulaganathan Baraneedharan , Thayakumar Allen , Thiyagarajan Saravanan , Brijwani Nilesh , Tewari Biplab , Santhappa Basavaraja U. , Radhakrishnan Padhma , Majumder Pradip K. 
Published: August 2015

Abstract
Predicting clinical response to anticancer drugs remains a major challenge in the treatment of cancer. Indeed, while biomarker-guided strategies for personalizing anticancer drugs have shown strong promise in certain cases, recent studies have shown that the tumor microenvironment and heterogeneity can limit the predictive power of biomarkers alone. Here we have engineered a personalized tumor ecosystems, termed CANScript™, that contextually conserve tumor heterogeneity and phenocopy the tumor ecosystem using thin tumor explants maintained in defined tumor grade-matched matrix support and autologous ligands from patients. We then demonstrated that the CANScript™ platform can be used to predict clinical response. Specifically, functional readouts obtained by exposing the CANScript™ ecosystems from more than 1100 patients to a panel of anticancer drugs, together with the corresponding clinical outcomes, were used to train a novel machine learning algorithm; the learned model was then applied to predict clinical response to anticancer drugs in a test group comprising of 900 new patients, where it achieved 100% sensitivity in its predictions while also keeping specificity in a desired high range. We have also observed that CANScript™ retains patient tumor immune environment which is important for clinical response of not only immunomodulators but other anti-cancer drugs. Here we report the effect of immunomodulators in refractory CRC tumors which remains difficult to treat. Data demonstrates that Anti-CTLA-4 has profound antitumor effect in refractory CRC tumors by increasing cytotoxic T-Cells. In this cohort of 16 patients’ tumors CANScript™ platform identifies 31% as responders (5/16) where conventional tumor sections culture model shows only 6% as (1/16) responders.
Citation Format: Biswanath Majumder, Baraneedharan Ulaganathan, Allen Thayakumar, Saravanan Thiyagarajan, Nilesh Brijwani, Biplab Tewari, Basavaraja U. Santhappa, Padhma Radhakrishnan, Pradip K. Majumder. Identification of responders for Anti-CTLA4 in refractory colorectal cancers using CANScript™ platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1304. doi:10.1158/1538-7445.AM2015-1304
Abstract 1313: Characterization and isolation of antigen-responding T cells in Sipuleucel-T treated patients
Authors: Pufnock Jeff , Vu Tuyen , Trager James , Sheikh Nadeem 
Published: August 2015

Abstract
Sipuleucel-T is an FDA-approved autologous cellular therapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate (mCRPC). Sipuleucel-T is manufactured from peripheral blood mononuclear cells (PBMCs) cultured with PA2024, a fusion antigen composed of prostatic acid phosphatase (PAP) fused to granulocyte macrophage-colony stimulating factor (GM-CSF). We have demonstrated that following three infusions this therapy results in T cell antigen specific responses directed against both PA2024 and PAP in treated patients. In this study we utilized the cellular dye Carboxyfluorescein succinimidyl ester (CSFE) and flow cytometric analysis to further characterize antigen responding T cells in Sipuleucel-T treated patients. We observed that CD4+ T cells predominate the antigen-responding T cell population following treatment, confirming our previous studies. Importantly, this approach has allowed us to also visualize a previously undetected population of antigen responding CD8+ T cells. The frequency of both of these populations is enhanced following treatment relative to baseline responses and the responding T cells display increased surface expression of the prototypical T cell activation markers CD134 and CD137 relative to non-proliferating T cells. Additionally, we are exploiting the increased surface expression of these activation markers on antigen-responding T cells to isolate these cells in an HLA and epitope-independent manner. Using this methodology we have demonstrated Sipuleucel-T is capable of inducing both CD4+ and CD8+ antigen-specific T cell responses in treated patients, and that we are capable of isolating these antigen-responding T cells specifically and with minimal manipulation.
Citation Format: Jeff Pufnock, Tuyen Vu, James Trager, Nadeem Sheikh. Characterization and isolation of antigen-responding T cells in Sipuleucel-T treated patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1313. doi:10.1158/1538-7445.AM2015-1313
Abstract 1349: Tim-3/galectin-9 interaction might be associated with the immunosuppression of gastrointestinal stromal tumor (GIST)
Authors: KOMITA HIDEO , Koido Sigeo , Tajiri Hisao , Suzuki Masafumi , Homma Sadamu 
Published: August 2015

Abstract
Purpose: Although GIST shows high expression of Wilms’ Tumor 1 (WT1) and might be potentially immunogenic, there are no evidences that antitumor immunity suppresses GIST development. Elucidation of the mechanism of the immunosuppression of GIST might contribute to the establishment of the immunotherapy against GIST.
Methods: Nineteen GIST tissue samples were evaluated for the expression of various tumor-associated antigens, MHC class I, immune check point molecules and the infiltration of immune cells by immunohistochemistry. Tumor infiltrating lymphocytes (TILs) from freshly resected GIST tissues were analyzed for WT1 tetramer assay.
Results: All GIST tissues showed diffuse WT1 expression but not GP-100, NY-Eso1, Melan A and MAGEA4. They all expressed MHC class I and WT1 tetramer positive CD8+T cells were found in TILs from some GIST tissues. Seven GIST tissues showed marked CD8+ T cell infiltration and the infiltration of CD8+T cells and NK cells was strongly correlated. However, all the immune cells infiltrated into GIST tissues were CD69 negative inactivated cells. Although PD-1/PD-L1 expression was not seen in GIST tissues, galectin-9 was expressed in tumor cells and Tim-3 was expressed on NK cells but not CD8+T cells in all the GIST tissues.
Conclusions: Galectin-9 on tumor cells and Tim-3 on infiltrated NK cells might be associated with the immunosuppression of GIST.
Citation Format: HIDEO KOMITA, Sigeo Koido, Hisao Tajiri, Masafumi Suzuki, Sadamu Homma. Tim-3/galectin-9 interaction might be associated with the immunosuppression of gastrointestinal stromal tumor (GIST). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1349. doi:10.1158/1538-7445.AM2015-1349
Abstract 136: Evaluation of reversible BTK inhibitors in cell lines with clinically relevant Ibrutinib resistance mutations
Authors: Choy Regina Wai-Yan , Burton Luciana , Young Wendy , Crawford James J. , Penuel Elicia , Belmont Lisa D. 
Published: August 2015

Abstract
Background
Ibrutinib, a small molecule inhibitor that covalently binds Cys481 of Bruton's Tyrosine Kinase (BTK), has recently been approved in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Although the majority of patients respond to this drug, eventually resistance develops. Known causes for resistance include the outgrowth of cancer cells with mutations in either the drug binding pocket of BTK or activating mutations in the downstream effector, PLCγ2.
Objective
To explore mechanisms of resistance to ibrutinib and evaluate the potential of next generation BTK inhibitors on ibrutinib resistant cancer, we selected for resistance in cultured lymphoma cells. We chose TMD8, a cell line model of diffuse large B-cell lymphoma (DLBCL) that has constitutive B-cell receptor signaling, and REC-1, an ibrutinib sensitive MCL line, to model resistance.
Methods
TMD8 and REC-1 were cultured in increasing concentrations of ibrutinib to generate resistant cell lines. Genetic changes that may account for resistance were evaluated using whole exome sequencing. Resistant cell lines were evaluated for sensitivity to a small panel of BTK inhibitors.
Results
We generated a TMD8 derived cell line that is 1000-fold resistant to ibrutinib. Whole exome sequencing revealed a C481Y mutation in BTK. Reversible inhibitors that are not reliant on this site may function as alternative inhibitors of C481 mutant BTK. Ibrutinib-resistant TMD8 cells were tested for response to novel, reversible BTK inhibitors. The potency was similar to or modestly reduced (3 to 10 fold) on the ibrutinib-resistant cells compared to the parental line. In addition, we generated ibrutinib-resistant cells derived from the REC-1 line. Unlike resistance generated in TMD8, REC-1 resistant cells harbor a L527W mutation in BTK and are resistant to all BTK inhibitors that we evaluated.
Conclusions
C481Y and L527W BTK mutations have been identified in CLL patients that have relapsed after response to ibrutinib, and C481S mutations have been identified in ibrutinib relapsed CLL and MCL patients. Our data suggest that reversible, next generation BTK inhibitors have the potential to be efficacious on ibrutinib relapsed patients that harbor mutations at C481 of BTK.
Citation Format: Regina Wai-Yan Choy, Luciana Burton, Wendy Young, James J. Crawford, Elicia Penuel, Lisa D. Belmont. Evaluation of reversible BTK inhibitors in cell lines with clinically relevant Ibrutinib resistance mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 136. doi:10.1158/1538-7445.AM2015-136