bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5660: Tumor cell death caused by INT230-6 induces protective T cell immunity
Authors: Bloom Anja C. , Bender Lewis H. , Walters Ian B. , Clark Katharine T. , Terabe Masaki , Berzofsky Jay A. 
Published: July 2017

Abstract
Standard care for many types of cancer involves systemic administration of cytotoxic agents. This may result in low drug concentration at tumor sites, which limits cell killing. More recently it has been shown that cytotoxic formulations designed for intratumoral delivery improve drug efficacy presumably by increasing drug concentration at the tumor site. Furthermore, it has been discovered that the mechanisms of anticancer agents extend beyond direct tumor cell lysis. One major aspect is that cell death often induces an immune response. Different types of cell death such as necrosis, apoptosis and autophagic cell death induced by cytotoxic agents trigger immune responses with varying degrees of inflammation and involving different types of immune cells. The ideal immune responses that may give maximum benefit to patients would be strong and long lasting anti-tumor T cell responses. In this study, a novel, tissue and cell diffusive cytotoxic formulation, INT230-6, was administered intratumorally over 5 sequential days into subcutaneous 300mm3 murine Colon26 tumors. Treatment resulted in regression from baseline of 100% of the tumors and up to 80% complete response (CR). We then analyzed the T cell responses in the protection induced by INT230-6. No animals achieved a CR after CD8 or CD8/CD4 double depletion at treatment onset, indicating a critical T-cell role in tumor regression. Mice with CRs were protected from re-challenge by either subcutaneous or intravenous re-inoculation of the Colon26. The protection was abrogated by CD4/CD8 double depletion prior to the re-challenge, indicating that immunological T cell memory was induced and was necessary for protection. Hence, INT230-6 given locally to treat tumors induces tumor-specific protective T cell immunity. Colon26 tumors express the endogenous retroviral protein gp70 containing the AH-1 CTL epitope. AH-1-specific CD8 T cells were detected in tumors of mice without treatment. However, these highly expressed PD-1. This was consistent with the observation that the PD-1 blockade enhanced the efficacy of INT230-6. Conversely, INT230-6 enhances the efficacy of checkpoint inhibitors.
Citation Format: Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Katharine T. Clark, Masaki Terabe, Jay A. Berzofsky. Tumor cell death caused by INT230-6 induces protective T cell immunity [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 5660. doi:10.1158/1538-7445.AM2017-5660
Abstract 5662: MEK inhibitors potentiate tumor immune surveillance by enhancing cancer cell response of IFNγ
Authors: Xie Mengyu , Zheng Hong , Beg Amer 
Published: July 2017

Abstract
FDA approved mitogen-activated protein kinase (MAPK) kinase (MEK) targeting inhibitors such as trametinib have recently been reported to enhance anti-tumor immunity in multiple preclinical models. It is hypothesized that the combination of such MEK inhibitors with immune checkpoint blockade will have synergistic effects and cause further tumor regression. Immune checkpoint inhibitors such as anti-PD-1 overcome immunosuppressive signaling in the activated T cells, yielding higher levels of Interferon-gamma (IFNγ) release. IFNγ plays a key role in a wide range of immune responses by direct activation of JAK-STAT1 pathway through the binding of IFNγ receptor. JAK-STAT1 regulates transcription of downstream effector genes that are involved in tumor immune surveillance. Many studies have shown that in cancer cells, transcription of T cell chemokines CXCL9,10,11, as well as PD-L1 and MHC-I are induced upon stimulation with IFNγ. While there are some recent studies indicating MEK inhibitors enhance T cell activity and function, here we report for the first time that targeted inhibition of MEK increases tumor cells response to IFNγ and results in significant upregulation of target genes including T cell chemokines, MHC-I, as well as PD-L1.
We treated a panel of 20 human lung cancer cell lines with MEK inhibitor U0126 followed by IFNγ stimulation, and showed that the expression of CXCL10 is significantly increased as compared to IFNγ stimulation alone. Furthermore, we found that instead of MEK inhibition, knock down of KRAS in the KRAS mutant cell lines such as A549 and H2122 results in more dramatic CXCL10 upregulation upon IFNγ stimulation. This indicates the potential of increasing tumor T cell infiltration upon MEK targeted therapy. Next, to elucidate the underlying molecular mechanism, we analyzed JAK-STAT1 pathway in mouse lung cancer cell lines LKR, 344, and colon cancer cell line CT26, in which trametinib mediated synergistic expression of CXCL9,10, 11 and MHC-I, PD-L1 were observed. The phosphorylation as well as total protein of JAK2, STAT1 are increased in cells that are pre-treated with trametinib, as compared to IFNγ stimulation alone. Treatment of JAK inhibitor Ruxolitinib as well as knockout of IFNγR1 in LKR cells completely abolishes CXCL10 expression. Importantly, trametinib enhanced response to PD-1 blockade in the lung tumor models. In conclusion, our study demonstrates that targeting MEK signaling in cancer cells increases the response of IFNγ through JAK-STAT1 pathway, which may potentially enhance immune surveillance and response to immune checkpoint blockade.
Citation Format: Mengyu Xie, Hong Zheng, Amer Beg. MEK inhibitors potentiate tumor immune surveillance by enhancing cancer cell response of IFNγ [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 5662. doi:10.1158/1538-7445.AM2017-5662
Abstract 5663: A potential role for NKG2A to influence post-transplant outcomes in multiple myeloma
Authors: Cooperrider Jennifer , Ciarlariello Paul D. , Hughes Tiffany , Williams Nita , Hofmeister Craig , Baiocchi Robert , Benson Don M. 
Published: July 2017

Abstract
While there is currently no clear consensus regarding optimal maintenance therapy after autologous stem cell transplant (autoSCT), the early post-transplant setting is a potential site of augmentation to improve post-transplant outcomes. We previously characterized stem cell graft lymphocytes in association with progression free survival (PFS) after autoSCT in multiple myeloma (MM), and showed that there was an inverse correlation between NKG2A expression on CD56dim NK cells and PFS. Therefore, we aimed to investigate a potential role for NKG2A modulation, especially in the post-transplant setting with maintenance chemotherapy. We performed immunophenotypic analyses of NK cells from patients in the immediate post-transplant setting as well as from patients at various time points after transplant on lenalidomide maintenance therapy. In the immediate post-transplant setting (mean time since transplant=13 days) NKG2A was upregulated on NK cells when compared with KIR2DL1 (p=0.001) and KIR2DL2 (p=0.002). Additionally, in immunophenotypic analyses of PBMC from MM patients on various treatments, patients receiving lenalidomide maintenance therapy that recently underwent stem cell transplant (mean time since transplant=0.53 years) had elevated NKG2A expression compared to patients receiving no treatment (p=0.029). Conversely, patients receiving lenalidomide maintenance therapy over years (mean time since transplant=4.21 years) after transplant showed reduced NKG2A expression compared to patients receiving no treatment (p=0.0161). In bone marrow aspirates from patients with MM, primary CD138-positive myeloma cells in the bone marrow express HLA-E, the cognate antigen for NKG2A, which makes the overexpression of NKG2A biologically relevant. These data suggest that the NKG2A/HLA-E checkpoint axis may be more biologically relevant than KIR in myeloma, particularly in the post-transplant setting. This has important potential implications for treatment, as it demonstrates that NKG2A could serve as a potential target for modulation in the immediate post-transplant setting to improve survival, especially in the setting of maintenance chemotherapy. Further investigation should be aimed delineating the potential effect of NKG2A modulation on immune recovery and tumor surveillance to increase survival in the post-transplant setting.
Citation Format: Jennifer Cooperrider, Paul D. Ciarlariello, Tiffany Hughes, Nita Williams, Craig Hofmeister, Robert Baiocchi, Don M. Benson. A potential role for NKG2A to influence post-transplant outcomes in multiple myeloma [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 5663. doi:10.1158/1538-7445.AM2017-5663
Abstract 5667: Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance
Authors: D'Errico Gabriele , Vallespinos Mireia , Alcala Sonia , Valle Sandra , Martin-Hijano Laura , Sainz Bruno 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths worldwide. This is largely due to the existence of a subpopulation of stem-like cells present within the tumor, known as cancer stem cells (CSCs) that drive metastasis and chemoresistance. In addition, we have now come to realize that the tumor-associated microenvironment not only provides structural support for tumor development, but more importantly the microenvironment provides cues to CSCs that regulate their biological properties. Chemotherapy often leads to apoptosis of cancer cells, and in previous studies we have shown that tumor-associated macrophages (TAMs) exponentially increase following chemotherapy. We hypothesized that TAMs, in response to chemotherapy-induced apoptosis, secrete factors that potentiate PDAC chemoresistance. In line with this hypothesis, we show that monocyte-derived macrophages cultured in the presence of apoptotic PDAC cells polarize towards an M2 pro-tumor phenotype and secrete factors that render naïve PDAC cells, specifically CSCs, resistant to Gemcitabine- or Abraxane-induced apoptosis, irrespective of mutations in p53. Importantly, chemoresistant cells showed increased sphere formation capacity and increased tumorigenesis as measured in an extreme limiting dilution assay in nude mice, confirming an enrichment in CSCs. Moreover, using a syngeneic orthotropic in vivo model of PDAC, we were able to significantly augment the anti-tumor potential of Gemcitabine by pharmacologically eliminating TAMs using clodronate liposomes. To determine the mechanism by which TAMs promote PDAC chemoresistance, we performed proteomic analyses on macrophage conditioned media and identified several proteins specifically induced and secreted when macrophages were co-cultured with apoptotic PDAC cells, including 14-3-3 protein zeta/delta (14-3-3ζ), a major regulator of apoptotic cellular pathways. We present additional data to show that TAM-seceretd 14-3-3ζ promotes CSC chemoresistance. Taken together, the sum of these data highlight a unique regulatory mechanism by which chemotherapy-induced apoptosis acts as a switch to initiate a pro-tumor/anti-apoptotic mechanism in PDAC, challenging the idea that apoptosis of tumor cell is therapeutically beneficial, at least when immune sensor cells, such as macropahges, are present.
Citation Format: Gabriele D'Errico, Mireia Vallespinos, Sonia Alcala, Sandra Valle, Laura Martin-Hijano, Bruno Sainz. Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance [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 5667. doi:10.1158/1538-7445.AM2017-5667
Abstract 5676: Functional pairing of immunomodulatory targets in anaplastic thyroid cancer
Authors: Chakraborty Sanjukta , Maniyar Rachana R. , Tuli Neha Y. , Rahoma Ghada Ben , Budenz Cameron , Singh Sarnath , Geliebter Jan , Tiwari Raj 
Published: July 2017

Abstract
Thyroid cancer is the most common type of endocrine malignancy that has an escalating global frequency. Although most well differentiated thyroid cancers (WDTC) are manageable and respond to current therapeutic modalities, undifferentiated anaplastic thyroid cancers (ATC) exhibit a dramatically different clinical behavior and poor prognosis. With the recent development of immunotherapies, targeted, well-defined treatment plans can demonstrate promising treatment outcomes in ATC patients. Precise immunological targets in ATCs with potential clinical relevance are unknown. Major progress has been made in last 5 years toward development of immune checkpoint inhibitors using anti-CTLA-4 and anti-PD-1/PD-L1 antibodies for cancer treatment which has made immunotherapies one of the mainstream treatment choices. Few additional members of the immunoglobulin superfamily of receptors, like LAG3, TIM3 and VISTA have recently been identified as potential checkpoint targets. Interestingly some of these molecules including TIM3 and PD-L1 promote tumor progression and immune escape. Identification of specific immunotherapeutic targets requirs a better understanding of the immune microenvironment in ATC. To this end we evaluated the expression of prominent co-stimulatory and co-inhibitory cell surface molecules by RT-PCR in three thyroid cancer cell lines - TPC-1 (papillary), CGTH-W-1 (follicular) and 8505C (anaplastic). We observed that many co-inhibitory molecules were upregulated in all three tumor cell lines. CTLA4, interestingly, had the highest expression in 8505C. Additionally we observed differential expression of BTLA, LAIR1, TIM3 and VISTA between TPC-1 and 8505C. LAG3, PD-1 and PD-L1 were also upregulated in 8505C compared to TPC-1. Similar pattern was observed with the expression of co-stimulatory molecules, CD40L and GITR . GITR has been shown to have a tumor suppressor function in multiple myeloma. Another co-stimulatory molecule OX40, which has shown promise in tumor recession when targeted, was upregulated in all three cell lines and 8505C showed the highest expression. Our findings suggest that the aggressive and less immunogenic phenotype of ATC might be attributed to the differential expression of these molecules. Targeting these immunomodulatory molecules in ATC warrants a better understanding of the crosstalk between them and it might provide an efficient means for the disease management.
Citation Format: Sanjukta Chakraborty, Rachana R. Maniyar, Neha Y. Tuli, Ghada Ben Rahoma, Cameron Budenz, Sarnath Singh, Jan Geliebter, Raj Tiwari. Functional pairing of immunomodulatory targets in anaplastic thyroid 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 5676. doi:10.1158/1538-7445.AM2017-5676
Abstract 5682: Circulating tumour DNA following decompression using selfexpandable metallic stent
Authors: Takahashi Goro , Yamada Takeshi , Iwai Takuma , Takeda Kohki , Koizumi Michihiro , Shinji Seiichi , Yokoyama Yasuyuki , Hara Keisuke , Furuki Hiroyasu , Watanabe Atsushi , Ohta Keiichro , Uchida Eiji 
Published: July 2017

Abstract
Background: Decompression using selfexpandable metallic stent (SEMS) has been reported to improve short-term outcomes in patients with malignant large bowel obstruction (MLBO). However, some reports suggest that SEMS worsen long-term survival. Conversely, trans-anal drainage tubes (TDT), which are similar to the ileus tubes widely used in Japan for MLBO, have had no reports suggesting reduced survival. SEMS worsen long-term survival by compressing tumor continuously and induce tumor cell death which can lead production of various types of mediator which could negatively affect prognosis. In this study, we investigated tumor cell death induced by decompression procedure by using circulating tumour DNA (ctDNA).
Methods: Plasma samples were obtained before and 1, 3 and 7 days after decompression. First, we purified circulating cell free DNA (ccfDNA) from 1 mL of plasma and measured the concentration using fluorometer. Second, we measured mutated fragment of ccfDNA (circulating tumour DNA) which is derived from tumor cell. Mutational analysis from the main tumour was performed using Ion PGM™ Sequencer following library preparation with Ampliseq CHPver.2 (Thermo Fisher Scientific). Each mutant fragment in ccfDNA was quantified using digital PCR (QuantStudio 3D® digital PCR system).
Results: We enrolled 30 patients (22 SEMS and 8 TDT). CcfDNA levels on day7 was significantly increased in the SEMS group (before; 623ng/ml, day7; 1455ng/ml, p=0.006) but TDT group. Sequencing result revealed that the average number of mutation per tumor was 3.7 (e.g. APC, TP53, and KRAS) out of 50 genes. Mutant fragments (ctDNA) were detected in the ccfDNA in all cases. Mutant fragment also increased after decompression in SEMS group(before; 6.2copies/μl, day3; 22.6copies/μl, p=0.03)but in TDT group.
Conclusion: SEMS insertions increased plasma levels of not only ccfDNA but also ctDNA in patients with MLBO. This indicated that SEMS would induce massive cancer cell death. This tumor cell death can drain various mediators, including DAMPs, into blood flow and may worsen prognosis of patients with MLBO. Conversely, TDT may not induce massive tumor cell death.
Citation Format: Goro Takahashi, Takeshi Yamada, Takuma Iwai, Kohki Takeda, Michihiro Koizumi, Seiichi Shinji, Yasuyuki Yokoyama, Keisuke Hara, Hiroyasu Furuki, Atsushi Watanabe, Keiichro Ohta, Eiji Uchida. Circulating tumour DNA following decompression using selfexpandable metallic stent [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 5682. doi:10.1158/1538-7445.AM2017-5682
Abstract 57: Generation and characterization of novel anti-glycan monoclonal antibody against acute myeloid leukemia
Authors: Teo Chong Kok , Chng Wee Joo , Choo Andre Boon Hwa 
Published: July 2017

Abstract
Hematological malignancies encompass a wide spectrum of cancers from hematopoietic and lymphoid tissues. Under this grouping, the various forms of leukemia, lymphoma and myeloma have been classified into more than 60 distinct disease types, each having particular clinical features and disease outcomes. Among these diseases, curative treatments with high long-term survival rate have been developed for some, e.g. Chronic Myeloid Leukemia, while such effective regimens are still unavailable for many others, e.g. Multiple Myeloma and Acute Myeloid Leukemia. In this study, a panel of antibodies was raised against SLAMF7, a cell surface marker that was associated to Multiple Myeloma. Among the antibodies, TAG-HC2 was surprisingly found to have preferential binding to SLAMF7 expressed on Acute Myeloid Leukemia (AML) cell lines instead. Characterization of TAG-HC2 revealed that the binding of TAG-HC2 to SLAMF7 requires the N-glycosylation of the antigen. Functionally, TAG-HC2 does not have non-specific binding to normal cell lines when tested via flow cytometry and immunohistochemistry. TAG-HC2, when complexed with saporin-conjugated secondary mAb, was able to internalize into and kill AML cell lines. These results suggest that TAG-HC2 has the potential to be developed into an Antibody Drug Conjugate against AML.
Citation Format: Chong Kok Teo, Wee Joo Chng, Andre Boon Hwa Choo. Generation and characterization of novel anti-glycan monoclonal antibody against acute myeloid leukemia [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 57. doi:10.1158/1538-7445.AM2017-57
Abstract 5706: Gene expression profile of peripheral blood mononuclear cells in breast cancer patients may be contribute to the identification and the immunological classification of breast cancer patients by blood test
Authors: Suzuki Eiji , Kawaguchi Kosuke , Sugimoto Masahiro , Pu Fengling , Uozumi Ryuji , Yamaguchi Ayane , Nishie Mariko , Tsuda Moe , Kotake Takeshi , Morita Satoshi , Toi Masakazu 
Published: July 2017

Abstract
It is reported that gene expression profile of peripheral blood mononuclear cells (PBMCs) exhibits unique gene expression signature in cancer patients including renal cell carcinoma, pancreatic cancer and lung cancer. Since pancreatic cancer diagnosis is difficult in not only early detection of the disease but also in the diagnosis itself, development of novel diagnostic tools in addition to conventional diagnostic strategy has been awaited. On the other hand, in breast cancer, because early diagnosis by mammography and ultra sound examination on breast is established successfully, exploration of gene expression profile of PBMCs may be important in terms of insight to host antitumor immune response aspects.
In the current study, we performed RNA sequencing (RNA-seq) analysis on RNA of PBMCs from 3 healthy volunteers, 6 early and 7 metastatic breast cancer patients including all phenotypes defined by ER, PgR and HER2. Genes that showed FDR&lt;0.05 and fold change of &lt;0.5 and 2.0&lt; in comparison of healthy volunteers and breast cancer patients were applied to clustering analysis by Ward method. We found significant unique gene expression signature between healthy volunteers and breast cancer patients. Furthermore, it was shown that HER2 overexpressing breast cancer patients, which breast cancer patients were divided into 3 clusters including HER2 type and other 2 different groups, seemed to be classified into healthy group different from other phenotypes of breast cancer patients.
These findings suggested that evaluation of gene expression patterns of PBMCs of breast cancer patients might distinguish breast cancer patients from healthy subjects and the gene expression signature of PBMCs which divided breast cancer patients into 3 groups might reveal immunologically important biologic properties such as response prediction of cancer immunotherapy including immune checkpoint inhibition treatment.
Citation Format: Eiji Suzuki, Kosuke Kawaguchi, Masahiro Sugimoto, Fengling Pu, Ryuji Uozumi, Ayane Yamaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Satoshi Morita, Masakazu Toi. Gene expression profile of peripheral blood mononuclear cells in breast cancer patients may be contribute to the identification and the immunological classification of breast cancer patients by blood test [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 5706. doi:10.1158/1538-7445.AM2017-5706