bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5592: Metformin improves immune function of exhausted peripheral CD8+ T cells derived from cancer patients
Authors: Watanabe Mototsugu , Eikawa Shingo , Shien Kazuhiko , Yamamoto Hiromasa , Shien Tadahiko , Soh Junichi , Doihara Hiroyoshi , Toyooka Shinichi , Miyoshi Shinichiro , Udono Heiichiro 
Published: July 2017

Abstract
Background: Immunotherapy has been developed and shown a drastic effect on several malignancies. However, in the tumor microenvironment, CD8+ tumor infiltrating lymphocytes (CD8+ TILs) are repeatedly exposed to tumor antigens and lose their anti-tumor activities. We have recently shown that metformin can show anti-tumor effect thorough improving immune function in mouse models. Increased numbers of such multifunctional CD8+ TILs have well correlated with tumor retardation, suggesting an underlying mechanism of metformin in tumor immunity. The objectives of this study are to evaluate the efficacy of metformin on human immune function.
Methods: We obtained peripheral blood mononuclear cells (PBMC) from healthy volunteers (HV) and cancer patients (CP) before and after taking metformin orally for about 2 weeks. We cultured the PBMC in a presence of stimulation with phorbol 12-myristate 13-acetate (PMA) / ionomycin in vitro for 6 hours. Expressions of markers for immune-check points (PD-1 and Tim-3) were examined together with accumulated intracellular cytokines, IFN-γ, IL-2 and TNF-α by flow cytometry analysis.
Results: We obtained consents for take part in our clinical research from 20 HV and 15 CP (10 breast cancer, 4 metastatic lung cancer and 1 primary lung cancer). CD8+ T cells which expressed both of PD-1 and Tim-3 derived from CP were higher than those of HV (p = 0.041). Increased production of multiple cytokines, IFN-γ, IL-2 and TNF-α was observed in CD8+ T cells of almost all cancer patients by metformin treatment and its increasement was significant (p &lt; 0.01), whereas marginal difference before and after metformin administration was detected in the samples from healthy volunteers so far (p = 0.051).
Conclusion: Metformin treatment might be useful in reversion of exhausted CD8+T cells in cancer bearing patients.
Citation Format: Mototsugu Watanabe, Shingo Eikawa, Kazuhiko Shien, Hiromasa Yamamoto, Tadahiko Shien, Junichi Soh, Hiroyoshi Doihara, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono. Metformin improves immune function of exhausted peripheral CD8+ T cells derived from cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5592. doi:10.1158/1538-7445.AM2017-5592
Abstract 5593: Inhibition of A2AR induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical and clinical studies
Authors: Willingham Stephen , Hotson Andrew , Ho Po , Choy Carmen , Walter Kim , Yusko Erik , Benzeno Sharon , Laport Ginna , Miller Richard , McCaffery Ian 
Published: July 2017

Abstract
Adenosine signaling via A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and limits the efficacy of immunotherapy, chemotherapy, CAR-T, and vaccines. CPI-444 is a potent and selective oral A2AR antagonist. Daily treatment of mice with CPI-444 led to dose-dependent inhibition of tumor growth in multiple syngeneic tumor models. Combining CPI-444 with anti-PD-L1 treatment synergistically eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that are poorly responsive to anti-PD-1 or anti-PD-L1 monotherapy. We have initiated a Phase 1/1b clinical trial to examine safety, tolerability, biomarkers, and preliminary efficacy of CPI-444 as a single agent and in combination with the anti-PD-L1 antibody, atezolizumab, in patients with non-small cell lung, melanoma, renal, triple negative breast, and other (bladder, prostate, head and neck, colorectal) tumors. Step 1 of the trial focused on determining the optimal dose and schedule for CPI-444; Step 2 is currently evaluating the efficacy of optimal CPI-444 dosing alone and with atezolizumab. In 48 patients treated in Step 1, CPI-444 was well tolerated with 1 Grade 3 or 4 treatment related adverse events. Preliminary evidence of clinical activity was observed in patients treated with single agent CPI-444, including patients who previously failed anti-PD-1 therapy. A pCREB-based pharmacodyamic assay showed that 100 mg, BID dose of CPI-444 resulted in a complete, sustained inhibition of A2AR on circulating immune cells. CPI-444 treatment alone or in combination with atezolizumab resulted in increased frequency of circulating CD8+PD-1+ cells and memory/effector subsets of CD4+ and CD8+ T cells. Substantial changes in TCR repertoire (Morisita Index &lt;0.9) were observed in both anti-PD-1 native and refractory patients and correlated to patient responses. CD73 expression, CD8+ infiltration, TREG distribution, and gene expression signatures are currently being evaluated in serial tumor biopsy specimens and will be presented. In total, this shows that CPI-444 is well tolerated in cancer patients, exhibits functional inhibition of adenosine signaling, and treatment is associated with activation of anti-tumor immunity and clinical activity.
Citation Format: Stephen Willingham, Andrew Hotson, Po Ho, Carmen Choy, Kim Walter, Erik Yusko, Sharon Benzeno, Ginna Laport, Richard Miller, Ian McCaffery. Inhibition of A2AR induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical and clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2017-5593
Abstract 560: A pan-inflammatory and precancerous disease analysis reveals key biological characteristics in chronic inflammatory diseases with high oncogenic risk
Authors: Zhang Chi , Yao Fang , Cao Sha , Sheng Tao , Liang Sen , Du Wei , Xu Ying 
Published: July 2017

Abstract
It has long been observed that cancer development tends to be associated with chronic inflammation. Recent epidemiology studies have suggested chronic inflammation may be causally linked to a larger number of sporadic cancers. In this work, we have conducted a Pan-inflammatory and precancerous diseases analysis by comparing the 173 transcriptomics data sets consisting 4073 disease and 2669 normal human tissue samples of 10 cancer prone and 8 cancer independent inflammatory diseases, 11 precancerous diseases or benign tumors and 20 cancer types, aiming to identify fundamental differences between cancer-prone chronic inflammations and cancer-independent chronic inflammations and what biological characteristics cause cancer initiation or increased oncogenic risk. By applying differential gene expression, co-expression network, our in-house immune cell deconvolution and machine learning based hypoxia/oxidative stress prediction methods on the collected data, we have discovered the cancer prone chronic inflammatory diseases consistently have: (1) elevated relative proportion of CD4+ T, Macrophage, and Neutrophil cells, (2) decreased CD8 + T, adipocyte, monocyte and B cells, (3) highly disorder tissue repair phase I - IV related pathways, (4) increased oxidative stress level associated with Macrophage and Neutrophil proportions, (5) elevated iron ion metabolism, (6) over expressed extracellular glycosaminoglycan metabolism and (6) suppressed mitochondrial activity. These analyses results strongly suggest that there is a necessary pathway for the majority or all chronic
inflammatory diseases to become cancerous, namely consecutively dysregulated tissue repair process, increased reactive oxygen species producing immune cells, damage of extracellular matrix, Fenton reaction and production of hydroxyl radical and dysregulated mitochondrial activity. We believe these new insights could provide highly useful information in guiding future studies of inflammation associated cancers.
Citation Format: Chi Zhang, Fang Yao, Sha Cao, Tao Sheng, Sen Liang, Wei Du, Ying Xu. A pan-inflammatory and precancerous disease analysis reveals key biological characteristics in chronic inflammatory diseases with high oncogenic risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 560. doi:10.1158/1538-7445.AM2017-560
Abstract 5605: Frequencies of HLA-Class I and II alleles between German patients with renal cell carcinoma and healthy controls can be different
Authors: Göbel Steffen , Kehlen Astrid , Bluemke Karen , Altermann Wolfgang , Schlaf Gerald , Fischer Kersten , Fornara Paolo , Wullich Bernd , Wach Sven , Taubert Helge W. 
Published: July 2017

Abstract
The human leukocyte antigen (HLA) system is a major part of the human immune system and has an impact on tumor initiation, tumor progression and immunosurveillance. Renal cell carcinoma tumors are considered to be immunogenic. Therefore, we studied the allele frequencies of four gene loci (HLA-A, -B, -C and HLA-DR) in a cohort of 106 German renal cell carcinoma (RCC) patients and in 201 healthy controls. HLA-A-C were determined using serological methods, whereas HLA-C12, C14, C16, C18 and HLA-DR were characterized through the use of standard molecular biological methods. The presence of HLA-A and HLA-B alleles did not differ significantly between RCC patients and healthy controls. However, the occurrence of the HLA-C*12 allele was significantly increased in German RCC patients compared with healthy controls (P &lt; 0.005; RR=2.3; Fisher’s exact test), whereas the occurrence of the HLA-DRB1*04 allele was significantly reduced in RCC patients compared with healthy controls (P &lt; 0.05; RR=0.7; Fisher’s exact test). But the presence of allele HLA-C*12 was not significantly associated with 10 years overall survival. We suggest that the frequency of HLA alleles can affect development of RCC and could add knowledge as predictive marker for future immunotherapies.
Citation Format: Steffen Göbel, Astrid Kehlen, Karen Bluemke, Wolfgang Altermann, Gerald Schlaf, Kersten Fischer, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Frequencies of HLA-Class I and II alleles between German patients with renal cell carcinoma and healthy controls can be different [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5605. doi:10.1158/1538-7445.AM2017-5605
Abstract 5624: Characterization of proliferation in multiple T-cell subsets in the CT26 murine colon carcinoma model by multi-color flow cytometry
Authors: Thayer Matt , Wong Alden , Draper David , Saims Dan , Wise Scott C. 
Published: July 2017

Abstract
The efficacy of immune-modulating anti-cancer therapeutic antibodies that have been FDA-approved in recent years, such as anti-CTLA-4, anti-PD-1 and anti-PD-L1, has altered the paradigm of cancer treatment. Subsequently, the growing interest in the development of new single agent and combination therapies with immune-modulatory effects has generated a need for more powerful immunophenotyping techniques capable of in-depth cell characterization and proliferation assessment. To this end, using the CT26 syngeneic murine colorectal cancer model we have developed an 8 color flow cytometry antibody panel that focuses on the identification of lymphocyte subsets and analysis of proliferation within them utilizing the high-throughput-capable 4-laser, 14-color Attune NxT Flow Cytometer (Thermo Fisher Scientific). Splenocytes from tumor-naïve and CT26 tumor-bearing C57BL/6 mice were stained with CFSE (carboxyfluorescein succinimidyl ester), an amine-reactive fluorescent dye which enables generational tracking for up to seven rounds of cell division, allowing for proliferation to be quantified. Splenocytes from these mice were then stimulated with anti-CD3, anti-CD28, and IL-2. After stimulation for four days, cells were stained with antibodies against CD45, CD3, CD19, CD49b, CD335, CD4, CD8, and FoxP3. We were able to identify differential proliferative capacity between naïve and tumor-bearing mice in CD4+ T-cell, CD8+ T-cell, regulatory T-cell, and B-cell populations. Finally, we show that the accuracy of analysis is enhanced by the use of fluorescence minus-one (FMO) controls to identify those markers that generate dim signals, as well as a viability dye used to exclude dead cells from analysis. Identification of potentially responsive immune compartments, as well as characterizing proliferation, will facilitate identification and development of potential combination therapies by expanding the depth of our ability to provide mechanistic descriptions of drug function and efficacy. Following this proof-of-concept work, we will also present data from tumor-bearing mice treated with immune checkpoint inhibitors in order to identify potential differences in proliferation after treatment with immune-modulating agents.
Citation Format: Matt Thayer, Alden Wong, David Draper, Dan Saims, Scott C. Wise. Characterization of proliferation in multiple T-cell subsets in the CT26 murine colon carcinoma model by multi-color flow cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5624. doi:10.1158/1538-7445.AM2017-5624
Abstract 5644: The emergence of resistance to tamoxifen in relation to menopausal status, HER-2 status, status of steroid receptor and lymph nodes metastases status
Authors: Maksimovic Sinisa 
Published: July 2017

Abstract
Background: The study used data from medical and counselling of patients who were diagnosed with hormonedependent breast cancer. Aim: The objective of the paper is to identify within a group of patients diagnosed with hormone sensitive breast cancer and those who have received adjuvant tamoxifen, and then to isolate the patients with whom the therapeutic effect of tamoxifen stopped.
Methods: The study analyzed 153 patients in the period from 2005 to 2011, at the Public Health Institution Hospital, Sveti Vračevi" in Bijeljina. Resistance to tamoxifen was developed by 60 patients (39.2%) and 93 patients (60.8%) did not develop resistance to it.
Results: More common emergence of resistance is in the premenopausal group of patients (p&lt;0.001). Statistically significant difference in frequency of resistance to tamoxifen was observed in the group of patients with ER-/PrR+ status of steroid receptors (p&lt;0.001). In relation to HER-2 status of diagnosed cancer, a statistically significant difference in frequency of resistance emergence during tamoxifen therapy in patients with HER2-positive status (p&lt;0.001) was observed. We found that there is a statistically significant difference between patients with metastatic in lymph nodes compared to patients who had no metastases in lymph nodes (X2=39.494; p&lt;0.001).
Conclusions: The analysis of menopausal status of patients, status of ER/PgR receptors status, HER-2 status of diagnosed cancer and status of lymph nodes trying to sort out the parameters on the basis of which a group of patients who can be expected to develop resistance to tamoxifen could be differentiated.
Note: This abstract was not presented at the meeting.
Citation Format: Sinisa Maksimovic. The emergence of resistance to tamoxifen in relation to menopausal status, HER-2 status, status of steroid receptor and lymph nodes metastases status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5644. doi:10.1158/1538-7445.AM2017-5644
Abstract 5655: Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer
Authors: Janson Christine , Jung Heiyoun , Ertl Linda , Liu Shirley , Dang Ton , Zeng Yibin , Krasinski Antoni , McMahon Jeff , Zhang Penglie , Charo Israel , Singh Rajinder , Schall Thomas J. 
Published: July 2017

Abstract
Pancreatic cancer is an aggressive malignancy with a 5 year survival rate of less than five percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which are reported to support tumor growth by suppressing host immune responses to the tumor. Recruitment of monocytes to various tissues, including tumors, is dependent upon activation of the chemokine receptor CCR2 by one or more of the chemokines CCL2, CCL8 and CCL13. In preclinical and clinical studies, inhibition of CCR2 in pancreatic cancer has shown to decrease tumor progression by blocking recruitment and accumulation of monocytes/macrophages in the tumor microenvironment. Analysis of human pancreatic tumors revealed elevation of both CCL2 and CSF1, which recruit monocytes, as well as the monocyte marker CD14, in advanced pancreatic cancers. Current immunotherapy using checkpoint inhibitors are effective in some tumors, but lack efficacy in immune insensitive cancers, including pancreatic cancer. Here, we report that the inhibition of CCR2 using a small molecule antagonist potentiates anti-PD-1 immunotherapy in a syngeneic, orthotropic mouse model of pancreatic cancer. Our data reveal that blocking CCR2 decreases tumor burden by blocking monocyte infiltration and creating a microenvironment more favorable for CD8 T cells activity, and provide a mechanistic rationale for investigating the combination of a CCR2 antagonist and an immune checkpoint inhibitor in pancreatic cancer.
Citation Format: Christine Janson, Heiyoun Jung, Linda Ertl, Shirley Liu, Ton Dang, Yibin Zeng, Antoni Krasinski, Jeff McMahon, Penglie Zhang, Israel Charo, Rajinder Singh, Thomas J. Schall. Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5655. doi:10.1158/1538-7445.AM2017-5655
Abstract 5657: Objective measurement and significance of VISTA (PD-1H) expression in non-small cell lung cancer (NSCLC)
Authors: Villarroel-Espindola Franz , Datar Ila J. , Velcheti Vamsidhar , Rimm David L. , Herbst Roy S. , Schalper Kurt A. 
Published: July 2017

Abstract
Introduction: VISTA (PD-1H) is a member of the B7 family of immune co-regulatory molecules and has been proposed as a novel anti-cancer immunotherapy target. The intra- and extracellular domains of VISTA show homology to PD-1 and PD-L1, respectively, suggesting a role in anti-tumor immune evasion. The expression of VISTA, its association with PD-1 axis components and biological role in human NSCLC are unknown.
Methods: Using multiplex quantitative immunofluorescence (QIF), we simultaneously measured the levels of VISTA (clone D1L2G, CST), PD-L1 (clone 405.9A11, CST) and PD-1 (clone EH33, CST) protein in 732 stage I-IV NSCLCs from 3 retrospective collections represented in tissue microarray format (cohort #1 [n=297, Yale], cohort #2 [n=329, Greece]; and cohort #3 [n=106, Yale]). To evaluate the tumor tissue distribution, VISTA was also selectively measured in cytokeratin+ tumor cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells and CD20+ B-lymphocytes. Associations between the marker levels, clinico-pathological-molecular variables and survival were studied.
Results: VISTA protein was detected in all NSCLCs, showed a membranous staining pattern and was localized predominantly in the tumor cells in 27.4% of cases; and in the stromal compartment in 98.5%. Although VISTA was detected in all major tumor infiltrating lymphocyte (TIL) subsets, the signal was higher in CD20+ B-cells than in CD3+ T-lymphocytes (P&lt;0.05); and in CD4+ helper than in CD8+ cytotoxic T-cells (P&lt;0.001). Using the median score as cut point, elevated VISTA in tumor and/or stromal cells was significantly associated with high PD-L1, PD-1 protein expression and increased CD8+TILs in the cohorts (P&lt;0.001 - P&lt;0.05). No consistent association between VISTA levels and age, gender, smoking status, specific NSCLC histology, stage, EGFR/KRAS mutations and overall survival was found.
Conclusion: VISTA is expressed in the majority of NSCLCs and shows differential distribution in tumor/stromal cells and TIL subsets, suggesting a complex function as a ligand and receptor. Elevated expression of VISTA in NSCLC is associated with increased PD-1 axis targets and cytotoxic T-cell density, indicating its possible modulation by pro-inflammatory signals. Our results support VISTA as a candidate target for anti-cancer immunotherapy in NSCLC alone or in combination with PD-1 axis blockers.
Citation Format: Franz Villarroel-Espindola, Ila J. Datar, Vamsidhar Velcheti, David L. Rimm, Roy S. Herbst, Kurt A. Schalper. Objective measurement and significance of VISTA (PD-1H) expression in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5657. doi:10.1158/1538-7445.AM2017-5657