bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1317: Biomarker evaluation for PD-1 targeted therapies in non-small cell lung cancer (NSCLC) patients
Authors: Kamphorst Alice O. , Pillai Rathi N. , Yang Shu , Akondy Rama , Koenig Lydia , Yu Ke , McCausland Megan , Sica Gabriel , Khuri Fadlo R. , Owonikoko Taofeek K. , Ramalingam Suresh S. , Ahmed Rafi 
Published: August 2015

Abstract
Sustained expression of programmed cell death (PD)-1 inhibitory receptor is a hallmark of exhausted T cells during chronic infections and cancer. PD-1 signaling inhibits T cell activation, and maintains T cells in a dysfunctional state. Notably, inhibition of PD-1 interactions with PD-L1 is able to restore function in exhausted T cells. Several clinical trials have now shown that PD-1 blockade therapy results in durable clinical benefits in advanced stage cancer patients refractory to other treatments, and efficacy has been reported in multiple tumor types. Nonetheless many patients do not respond to PD-1 targeted therapies, hence a better understanding of the immunological responses induced by PD-1 pathway blockade and identification of predictive biomarkers is imperative. In this ongoing study we have analyzed peripheral blood mononuclear cells (PBMC) from advanced stage NSCLC patients, before and during the course of PD-1 pathway blockade therapy. We find that CD8 T cell activation is observed in some patients following therapy, but it is not consistently associated with clinical response. Interestingly, treatment-induced CD8 T cell proliferation is not sustained in some patients even with continuation of therapy. After PD-1 pathway blockade, we find co-expression of CTLA-4 on proliferating PD-1+ CD8 T cells in the blood. Accordingly, we found that tumor infiltrating CD8 T cells expressing high levels of PD-1 also co-express CTLA-4 (and Tim-3) in surgical specimens of patients with NSCLC. We will present additional data on CD8 and CD4 T cells in NSCLC patients enrolled in PD-1 targeted therapies clinical trials and discuss potential biomarkers. We conclude that peripheral blood analysis can provide valuable insights into anti-cancer effects of PD-1 targeted therapy.
Citation Format: Alice O. Kamphorst, Rathi N. Pillai, Shu Yang, Rama Akondy, Lydia Koenig, Ke Yu, Megan McCausland, Gabriel Sica, Fadlo R. Khuri, Taofeek K. Owonikoko, Suresh S. Ramalingam, Rafi Ahmed. Biomarker evaluation for PD-1 targeted therapies in non-small cell lung cancer (NSCLC) 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 1317. doi:10.1158/1538-7445.AM2015-1317
Abstract 1323: Both programmed cell death protein 1 and programmed death-ligand 1 molecules can be expressed on the cell surface of small-cell lung cancer
Authors: Yamane Hiromichi , Isozaki Hideko , Ochi Nobuaki , Kudo Kenichiro , Honda Yoshihiro , Yamagishi Tomoko , Kubo Toshio , Kiura Katsuyuki , Takigawa Nagio 
Published: August 2015

Abstract
Background: Programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) play a major role in suppressing the immune system by forming the PD-1/PD-L1 complex, which transmits an inhibitory signal to reduce T-cell activity. PD-L1 is often expressed in various malignant tumors. On the other hand, PD-1 is generally observed in activated lymphocytes and myeloid-derived dendritic cells. Of the malignant cells, only Jurkat cells (under special conditions) and angioimmunoblastic T-cell lymphoma tissue cells express PD-1 on their surface.
Purpose: To clarify whether PD-1/PD-L1 complex participates in the immunotolerance on small-cell lung cancer (SCLC) cells.
Materials and methods: We examined the expression levels of PD-1 and PD-L1 on the cell surface of SCLC cell lines using flowcytometry and reverse transcription polymerase chain reaction. Subsequently, the soluble PD-L1 (sPD-L1) concentration was measured using enzyme-linked immunosorbent assay, and the cell growth inhibitory effect of IFN-γ was determined by direct cell counting using a hemocytometer and Trypan blue staining.
Results: Among the four SCLC cell lines examined, only SBC-3 cells expressed both PD-1 and PD-L1. The sPD-L1 concentrations in culture medium gradually increased according to cell growth. Although IFN-γ alone inhibited the growth of SBC-3 cells, PD-L1 expression on the cell surface was not induced by IFN-γ.
Conclusions: We demonstrated that both PD-1 and PD-L1 molecules are co-expressed on the surface of SCLC cells. Although the biological implications of this remain unclear, we speculate that PD-1 and its ligand on the SCLC cells may participate in the growth inhibition of tumor cells as is reported in cytotoxic T cells.
Citation Format: Hiromichi Yamane, Hideko Isozaki, Nobuaki Ochi, Kenichiro Kudo, Yoshihiro Honda, Tomoko Yamagishi, Toshio Kubo, Katsuyuki Kiura, Nagio Takigawa. Both programmed cell death protein 1 and programmed death-ligand 1 molecules can be expressed on the cell surface of 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 1323. doi:10.1158/1538-7445.AM2015-1323
Abstract 1334: Chemotherapy regulated microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small-cell lung cancer
Authors: Yagishita Shigehiro , Fujita Yu , Fujimoto Yuichi , Takahashi Fumiyuki , Takahashi Kazuhisa , Tamura Tomohide , Koizumi Fumiaki 
Published: August 2015

Abstract
Small-cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. Human epidermal growth factor receptor 2 (HER2) is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2-targeted therapy for SCLC remains unclear. Here, we firstly identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR-125b bound to the 3′-untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay we demonstrated a significant synergistic cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the synergistic anti-tumor effect of these agents in an orthotopic lung cancer model in vivo. Our result offer a novel therapeutic strategy for HER2-positive SCLC by using trastuzumab combined with cytotoxic drugs.
Citation Format: Shigehiro Yagishita, Yu Fujita, Yuichi Fujimoto, Fumiyuki Takahashi, Kazuhisa Takahashi, Tomohide Tamura, Fumiaki Koizumi. Chemotherapy regulated microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in 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 1334. doi:10.1158/1538-7445.AM2015-1334
Abstract 1337: Up-regulation of mannose 6-phosphate receptor induced by BRAF inhibitor PLX4720 is linked to phosphatidylserine externalization and shows positive effects for combination therapies
Authors: Lavilla-Alonso Sergio , Brekken Rolf , Gabrilovich Dmitry 
Published: August 2015

Abstract
New therapies of metastatic melanoma, including BRAF inhibitors, check-point blockade or adoptive T-cell transfer, hold high promise. However, their efficacy remains unsatisfactory. Combination of different modalities offers an opportunity to enhance their effect. We studied mannose 6-phosphate receptor (MPR) previously implicated in synergistic effect of cancer chemotherapy and immunotherapy. Approximately 50% of human melanomas bear the activating mutation V600E in BRAF that can be selectively targeted with BRAF inhibitor PLX4720. We have observed that in vitro treatment of human V600E-positive melanoma cells 451Lu and WM983B leads to a dose-dependent up-regulation of mannose 6-phosphate receptor (MPR) in the cell surface. An increase in cell surface MPR, enhanced recombinant Granzyme B uptake, a requirements for effective combination with immunotherapy. This effect of PLX4720 on MPR expression was reproduced in a mouse model featuring xenograft 451Lu-derived subcutaneous tumors. This effect was limited only to sensitive cell lines, disappearing completely after resistance had been induced by extended treatment with growing doses of the drug. We have previously determined that autophagy has a key role in MPR up-regulation after chemotherapy or radiation therapy. However, in the case of PLX4720, autophagy occurs 1-2 days after the start of the treatment while membrane MPR was up-regulated not early than 3-4 and 10-14 days after the start of the treatment in 451Lu and WM983B cells respectively. In addition, autophagy was present independently of whether the cells were resistant to PLX4720 or not. These data indicate that autophagy was probably not responsible in PLX4720 inducible up-regulation of MPR. We observed a parallel changes in MPR up-regulation and phosphatidylserine (PS) externalization in live melanoma cells. PS and MPR co-localized on cell surface after the treatment with PLX4720. Co-incubation of PLX4720 with PS-specific antibody resulted in an ablation of the subsequent membrane MPR up-regulation. These observations help to explain the synergism between immunotherapy and targeted therapy of melanoma and to design clinical trials.
Citation Format: Sergio Lavilla-Alonso, Rolf Brekken, Dmitry Gabrilovich. Up-regulation of mannose 6-phosphate receptor induced by BRAF inhibitor PLX4720 is linked to phosphatidylserine externalization and shows positive effects for combination therapies. [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 1337. doi:10.1158/1538-7445.AM2015-1337
Abstract 134: CCN5 down regulates HER2/ neu expression in HER2 positive breast cancer cells
Authors: Sarkar Sandipto , Maity Gargi , Das Amlan , Majumder Monami , Banerjee Snigdha , Banerjee Sushanta 
Published: August 2015

Abstract
Breast cancers are broadly classified into four different subtypes which are Luminal A, Luminal B, Basal type and Her2 positive cancers. The cells in Her2 positive tumor lesions overexpress the tyrosine kinase receptor ErbB2 or Her2 which serve as the major oncoprotein and drives the unrestrained proliferation of the cells which is one of the major hallmarks of cancer. About 25% of the breast cancer overexpress Her2 (ErbB2) proto-oncogene resulting in aggressive tumor phenotype and is associated in poor prognosis in patients. Though Her2 targeted therapies are being used hugely in clinical practice, a significant fraction of the Her2 positive tumors develop mechanisms to evade the targeted therapies of Her2 inhibition. CCN5 or Wisp2 is a matricellular protein which is now considered as an ‘anti-invasive gene’. It has been already that established from multiple evidences that CCN5 protein inhibits progression of triple negative breast cancer. The goal of the study is to investigate if CCN5 can regulate Her2 in Her2 positive breast cancer. We have found that CCN5 treatment also negatively regulates expression and activity of Her2 receptor in Her2 overexpressed breast cancer cells. It has been indicated from Her2 promoter assays that Wisp2/CCN5 negatively regulates the expression of Her2 in a transcriptional level. Wisp2 /CCN5 treatment of Her2 overexpressed breast cancer cell lines, SKBR3 and Bt474, exerts a negative impact on the migration and proliferative properties of the cancer cells. Thus it can be concluded that our initial studies on effect of CCN5 on Her2 positive cells can pave the way for a novel approach of therapy to control Her2 overexpressed tumor cell growth.
Citation Format: Sandipto Sarkar, Gargi Maity, Amlan Das, Monami Majumder, Snigdha Banerjee, Sushanta Banerjee. CCN5 down regulates HER2/ neu expression in HER2 positive breast cancer cells. [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 134. doi:10.1158/1538-7445.AM2015-134
Abstract 1348: CD4 T cells targeting citrullinated vimentin reject advanced tumors
Authors: Durrant Lindy G. , Brentville Victoria A. , Metheringham Rachael L. , Daniels Ian , Symonds Peter , Gijon Mohamed , Xue Wei 
Published: August 2015

Abstract
CD4 cells are potent effectors but CD4 responses to tumour associated antigens are attenuated. Cellular stress induces autophagy which leads to modification of proteins recognised by the immune system. In the absence of inflammation, immunity is regulated, whereas in its presence CD4 responses to modified self-antigens are stimulated. T cells commonly target modified self-antigens and have been shown to play a role in the pathophysiology of several autoimmune diseases. In this study the ability of these CD4 cells to target cancer has been explored. One modification is conversion of arginine to citrulline. Peptidylarginine deiminases (PADs), are a family of calcium dependent enzymes found in a variety of tissues, where their role is post translation citrullination of proteins. Citrullination is conversion of the positively charge aldimine group ( = NH) group of arginine to the neutrally charged ketone group ( = O) of citrulline. Immunisation with citrullinated vimentin peptides induced IFNγ and granzyme B secreting CD4 T cells in response to autophagic tumour targets. The induced CD4 responses to citrullinated self-peptide epitopes show minimal reactivity to the unmodified sequence. A single immunization with modified peptide, up to 14 days after tumour implant, resulted in long term survival in 60-90% of animals with no associated toxicity. The anti-tumour responses were dependent upon CD4 but not on CD8 T cells. This study provides the first evidence that tumours can present citrullinated peptides that can be targets for CD4 cells. This presentation is dependent upon autophagy and PAD enzymes. The CD4 T cells release IFNγ and show direct cytotoxicity which results in potent anti-tumour responses in vivo. This approach is being fast tracked into the clinic in patient's whose tumours express vimentin. This could be patients with mesenchymal tumours or in patients whose tumours undergo epithelial to mesenchymal transition as vimentin is one of the first proteins to be expressed in this transition.
Citation Format: Lindy G. Durrant, Victoria A. Brentville, Rachael L. Metheringham, Ian Daniels, Peter Symonds, Mohamed Gijon, Wei Xue. CD4 T cells targeting citrullinated vimentin reject advanced 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 1348. doi:10.1158/1538-7445.AM2015-1348
Abstract 1355: Functional inactivation of LKB1 increases the production of pro-inflammatory cytokines and governs response to immune modulation
Authors: Akbay Esra A. , Koyama Shohei , Li Yvonne , Herter-Sprie Grit S. , Thai Tran C. , Aref Amir R. , Soucheray Margaret , Shimamura Takeshi , Barbie David A. , Dranoff Glenn , Hammerman Peter S. , Wong Kwok-Kin 
Published: August 2015

Abstract
LKB1/STK11 is one of the most commonly mutated tumor suppressors in non-small cell lung cancers. Inactivation of LKB1/STK11 is common in lung cancers with mutated KRAS alleles (1) and results in a clinically more aggressive and metastatic phenotype (2-5). Here, we show in genetically engineered mouse models (GEMMs) and in primary human cancer specimens that loss of LKB1/STK11 in the context of mutated KRAS has a marked effect on the tumor immune microenvironment characterized by accumulation of neutrophils and of tumor promoting cytokines including interleukin (IL)-6. Importantly, Kras/Lkb1 tumors also carry reduced number of tumor-infiltrating lymphocytes with the infiltrating lymphocytes expressing higher levels of T cell exhaustion markers and greater proportions of regulatory T cells as compared to KRAS-driven (Kras) tumors. We also found that presence of LKB1 mutation was negatively correlated with programmed death-1 ligand-1 (PD-L1) expression in mouse and human lung tumors and that antibodies therapeutically targeting this immune checkpoint were ineffective in Kras/Lkb1 mice. In contrast, an IL-6 neutralizing antibody showed clinical benefit in the Kras/Lkb1 model via the reduction of neutrophil accumulation and proinflammatory cytokines. These findings suggest that LKB1 loss of function exacerbates the tumor inflammatory microenvironment in lung cancers and that targeting the aberrant cytokine signaling in LKB1-deficient tumors could be a viable therapeutic option.
Citation Format: Esra A. Akbay, Shohei Koyama, Yvonne Li, Grit S. Herter-Sprie, Tran C. Thai, Amir R. Aref, Margaret Soucheray, Takeshi Shimamura, David A. Barbie, Glenn Dranoff, Peter S. Hammerman, Kwok-Kin Wong. Functional inactivation of LKB1 increases the production of pro-inflammatory cytokines and governs response to immune modulation. [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 1355. doi:10.1158/1538-7445.AM2015-1355
Abstract 1359: Co-expression of ULBP1 and NKG2D are related to better overall survival in patients with gastric cancer
Authors: Yoshimura Kiyoshi , Inoue Moeko , Kamei Ryoji , Kitano Shigehisa 
Published: August 2015

Abstract
Objective
The relationship between expressions of ULBP1/NKG2D and their clinicopathological outcome in patients with gastric cancer were investigated.
Background
ULBP1 which is one of NKG2D ligand and expressing on tumor cell surface binds to the NKG2D receptor presenting on NK, CD8+ T and gamma delta T cell. It was considered that innate immunity is mainly induced through the interaction between ULBP1 and NKG2D. The role of this immune response is not clear yet, and is controversial whether it is inhibited or activated signal.
Methods
We performed immunohistochemical staining of gastric cancer tissue with antibody against ULBP1 and NKG2D in 98 patients who received surgery in 2004 to 2008. We investigated expression of ULBP1 in tumor and NKG2D in mononuclear cells around tumor by multiple points observation. These results were compared to their association with histological and clinical outcome.
Results
The positive group of NKG2D expression on mononuclear cells around gastric cancer tissue had significantly longer overall survival (OS) than the negative group (p = 0.0217). Although it was not recognized significant difference of ULBP1 expression on gastric cancer cells, in a combination of ULBP1 and NKG2D expression, both positive group had best OS, and both negative group had poorest OS in this study.
Conclusion
The interaction between ULBP1 and NKG2D in gastric cancer may have positive signal which relates to good OS. Although the mechanism of immune system through ULBP1/NKG2D is controversial, we obtained an interesting result according to this mechanism.
Citation Format: Kiyoshi Yoshimura, Moeko Inoue, Ryoji Kamei, Shigehisa Kitano. Co-expression of ULBP1 and NKG2D are related to better overall survival in patients with gastric 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 1359. doi:10.1158/1538-7445.AM2015-1359
Abstract 1363: VEGF reduction facilitates angiogenesis by CXCR2
Authors: Kosir Mary A. , Ju Donghong 
Published: August 2015

Abstract
PURPOSE: With multiple pathways for angiogeneis, the purpose of the study is to quantify the expression of angiogenic tyrosine kinase receptors during endothelial tubule formation while inhibiting a G-protein linked CXCR2 receptor that binds angiogenic CXC chemokines.
METHODS: Using endothelial tubule formation assays on Matrigel and Growth Factor Reduced (GFR) Matrigel, and without added VEGF, human umbilical vascular endothelial cells (HUVEC) were treated with a selective small molecule non-peptide inhibitor of CXCR2 called SB225002 (N-(2-hydroxy-4-nitrophenyl)-N9-(2-bromophenyl)urea compared with control. Previous dose-inhibition curves established optimal dosing of SB225002. After 6 hours of incubation, endothelial tubule formation was quantified by counting tubule length in four random microscopic fields using the microscope camera software NIS-Elements AR 3.10 in triplicate and compared to control. In parallel, endothelial cells were collected from the Matrigel under the same conditions for quantification of angiogenesis receptors and growth factors by RT-PCR in triplicate.
RESULTS: There was significant inhibition of endothelial tubule formation on Matrigel (and GFR Matrigel) by the addition of SB225002 (40-58% of inhibition) under conditions of no added VEGF when compared to control. The expression of mRNA in HUVEC cells harvested from Matrigel was not different for VEGFR1-3, FGFR1-3, and PDGFRA,B with or without the inhibitor. Under conditions of no added VEGF, the expression of CXCR2 mRNA was the same with or without the inhibitor, but the endothelial tubule formation was significantly inhibited.
CONCLUSION: Under growth factor reduced conditions, including no added VEGF, the endothelial tubule formation and angiogenenic tyrosine kinase receptor expression was similar to standard matrigel. However, when a selective non-peptide inhibitor of CXCR2 (SB225002) was added, endothelial tubule formation was inhibited without change in expression of other angiogenesis receptors from HUVEC cells retrieved from the matrigel. Therefore, tubule formation continues with the chemokine/CXCR2 axis and may be an additional pathway that circumvents other attempts at angiogenesis inhibition targeting tyrosine kinase inhibitors.
Citation Format: Mary A. Kosir, Donghong Ju. VEGF reduction facilitates angiogenesis by CXCR2. [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 1363. doi:10.1158/1538-7445.AM2015-1363