bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4545: Quantitative profiling of Cytochrome P450 2S1 in colorectal cancer by PRM assay
Authors: Shaheed Sadr ul , Patterson Laurence H. , Pors Klaus , Sutton Chris W. 
Published: August 2019

Abstract
Introduction: Cytochromes P450s (CYPs) constitute a superfamily of xenobiotic metabolising enzymes responsible for metabolism of many pharmaceuticals in the liver. Elevated mRNA levels of specific isoforms, such as CYP2S1, are associated with poor prognosis in colorectal cancer (CRC), and represent novel therapeutic targets for biotransformation of prodrugs to potent cytotoxics at the cancer site. In order to understand the expression of CYP2S1 protein, we have developed a parallel reaction monitoring mass spectrometry (PRM MS) assay to screen CRC samples.
Method: Peptides (n=3) uniquely associated with CYP2S1 were synthesized and used as standards to optimise analytical performance (fragmentation conditions, LC retention time, LOQ, LOD, dynamic range) in an Orbitrap Fusion-based PRM MS assay. Levels of CYP2S1 were then determined in protein extracts of CRC, relative to the standards.
Results: The PRM MS assay yielded quantitative data over 3 orders of magnitude. CYP2S1 was detected in C106, CaCO2, HCC2998, HT55 and DLD1 cell lines (0.05-1.08pg) and HT55 and DLD1 xenografts (0.29-0.41pg). CYP2S1 was also detected in patient-specific CRC tissues, with elevated levels in Stage III tumours.
Conclusions: The PRM MS assay provides a specific, sensitive, high throughput method for identifying CYP2S1 compared to established enzyme and immunoassays. CYP2S1 levels vary considerably across CRC sources highlighting the importance of screening to identify the correct models for new drug development and the right patients for subsequent treatment.
Citation Format: Sadr ul Shaheed, Laurence H. Patterson, Klaus Pors, Chris W. Sutton. Quantitative profiling of Cytochrome P450 2S1 in colorectal cancer by PRM assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4545.
Abstract 4546: Functional cell surface proteomics of acute myeloid leukemia enables predictive modeling of antibody-drug conjugate cytotoxicity
Authors: Lawrence Robert , Thurman Robert , Biechele Travis , Tognon Cristina , Savage Samantha , Schultz Anna Reister , Tyner Jeffrey , Arthur William 
Published: August 2019

Abstract
Acute myeloid leukemia (AML) remains a significant unmet medical need. The development of targeted therapies for AML is challenging due to the heterogeneity of immunological and genetic disease subtypes and physiological similarities shared by blasts and normal myeloid progenitor cells. The identification of abundant cell surface markers on AML blasts with limited expression on bone marrow progenitors could drive the development of novel antibody-drug conjugates (ADCs) and other antibody-based therapeutics with improved therapeutic windows. Here we used hydrazide chemistry and mass spectrometry-based proteomics to profile the cell surface landscape of 95 primary blast samples from the Beat AML research consortium and normal bone marrow progenitor cells from healthy donors. We measured the abundance of over 5,000 proteins with high reproducibility (R2 = 0.89) and coverage of known cell surface markers (240/371). We also identified more than 2,500 N-glycosylation sites, many of which are predicted by canonical sequence motifs but have not been demonstrated experimentally. These findings thereby expand our knowledge of both the AML and normal hematological cell surface proteome. Additionally, we used pulsed stable isotope labeling coupled with the aforementioned hydrazide method to assess global surface protein abundance and turnover dynamics in a panel of malignant cell lines. We integrated our cell surface characterization with Beat AML’s mRNA expression, mutation, and AML subtype classification data to prioritize proteins for further exploration as candidate targets for ADC therapeutics. We generated a library of ADCs using monoclonal antibodies conjugated with Auristatin T, a highly potent membrane impermeable microtubule inhibitor, and measured ADC cytotoxic activity on a panel of AML cell lines as well as primary bone marrow progenitor cells. We used these integrated datasets to more precisely refine AML subtypes and identify patient populations that could benefit from novel AML ADCs. We report the preclinical validation of CD317 as a proof-of-concept for the utility of cell surface proteomics to identify novel targets for ADC therapeutics.
Citation Format: Robert Lawrence, Robert Thurman, Travis Biechele, Cristina Tognon, Samantha Savage, Anna Reister Schultz, Jeffrey Tyner, William Arthur. Functional cell surface proteomics of acute myeloid leukemia enables predictive modeling of antibody-drug conjugate cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4546.
Abstract 4549: Macrophage-epithelial metabolic crosstalk impairs chemotherapy in pancreatic cancer
Authors: Halbrook Christopher J. , Pontious Corbin , Kovalenko Ilya , Lapienyte Laura , Dreyer Stephan , Zhang Yaqing , Nelson Barbara , Hong Hanna , Chang Daivid , Morton Jennifer P. , Magliano Marina Pasca di , Lyssiotis Costas A. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDA) remains a leading cause of cancer related death, contrasting a relatively low incidence rate. A principle barrier in PDA treatment is the physiology of the tumors, characterized by a densely fibrotic stroma, rich with immune cell infiltration including macrophages. Macrophages are polarized by environmental cues which dictate their function. In PDA, macrophages within the tumor (tumor associated macrophages, or TAMs) are strongly immunosuppressive, inhibiting both infiltration and activation of cytotoxic T-cells. Additionally, TAMs have been shown to drive resistance to chemotherapy, though the mechanism for which remains unclear.
Several pathways have been described by which PDA cells recruit and polarize macrophages into TAMs, and the effects that TAMs have on the tumor microenvironment. These pathways have largely focused on signaling proteins, however, metabolic byproducts also influence the behavior of immune cells within the tumor microenvironment. To explore potential metabolic crosstalk, we have profiled the metabolic factors exchanged between PDA cells and TAMs. Among these, we have found that TAMs release metabolites which can regulate the response of PDA cells to chemotherapy. Importantly, this response is consistent across several murine and patient-derived pancreatic cancer cell lines, and this metabolite release appears to be a general property of anti-inflammatory macrophage metabolism. We further validated these findings in vivo, using a combination of pharmacological and genetic models to modulate myeloid cells within the tumor microenvironment. Taken together, these data suggest that further development of interventions which target either PDA-mediated polarization of TAMs or TAM-mediated inhibition of chemotherapy represent opportunities to improve the efficacy of currently available treatment options.
Citation Format: Christopher J. Halbrook, Corbin Pontious, Ilya Kovalenko, Laura Lapienyte, Stephan Dreyer, Yaqing Zhang, Barbara Nelson, Hanna Hong, Daivid Chang, Jennifer P. Morton, Marina Pasca di Magliano, Costas A. Lyssiotis. Macrophage-epithelial metabolic crosstalk impairs chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4549.
Abstract 4562: Intra-tumor immune activity is linked to genetic diversity of tumor infiltrating lymphocyte and impact clinical outcomes in hepatocellular cancer
Authors: Kawaguchi Tstutomu , Yan Li , Takahashi Hideo , Qi Qianya , Peng Xuan , Takabe Kazuaki , Otsuji Eigo 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) remains the second leading cause of the cancer-related death worldwide. Ongoing clinical trials with immune checkpoint inhibitors (CPIs) for HCC have revealed considerable amount of patients do not respond. Hence, to identify the responder is imminent need for immunotherapy in HCC. We aimed to examine the immune landscape of HCC, using the publically available data set The Cancer Genome Atlas (TCGA). Clinicopathological and genomic expression data in 371 patients with HCC were obtained from TCGA. CYT was defined by GZMA and PRF1 expression, and CIBERSORT and TIMER were used to evaluate intra-tumoral immune cell composition. Kaplan-Meier curve for overall survival (OS), disease free interval (DFI), progression free interval (PFI), and disease-specific survival (DSS) were obtained and Cox Progression Hazards model was used for multivariable analysis. Gene Set Enrichment Analysis (GSEA) was also conducted to analyze the gene sets enriched in CYT-High HCC patients. High CYT was associated with high levels of activated CD8+ T cells, gamma-delta T cells, M1 macrophages, and memory CD4+T cells on CYBERSORT. A similar result was also obtained on TIMER. CYT-high HCC patients had significantly improved DFI, PFI, DSS, and OS, compared to CYT-low HCC patients. The levels of immune checkpoint molecules (ICMs), including programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), PD-L2, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), indoleamine 2,3-dioxygenase 1 (IDO1), and IDO2, correlated significantly with CYT. High-CYT tumors showed increased somatic copy number alterations (SCNA). Gene expression of APOBEC3 family was significantly higher in high-CYT tumors compared to low-CYT tumors. T-cell and B-cell receptors was more diverse in High-CYT tumors compared to low-CYT tumors. Multivariate survival analysis demonstrated high CYT was an independent protective factor for prognosis in patients with HCC. High CYT is associated with significantly improved survival in HCC, secondary to enhanced immunity and increased cytolytic activity by T cell and M1 macrophage. Additionally, high CYT is associated with ICMs, and CYT can be a potential biologic marker for CPIs.
Note: This abstract was not presented at the meeting.
Citation Format: Tstutomu Kawaguchi, Li Yan, Hideo Takahashi, Qianya Qi, Xuan Peng, Kazuaki Takabe, Eigo Otsuji. Intra-tumor immune activity is linked to genetic diversity of tumor infiltrating lymphocyte and impact clinical outcomes in hepatocellular cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4562.
Abstract 4564: Tumor infiltrating lymphocytes are associated with p16 protein expression in acral lentiginous melanoma
Authors: Nino Marco A. Galvez , Castillo Miluska , Bernabe Luis A. , Casavilca sandro , Villegas Valeria , Sanchez Joselyn , Dunstan Jorge , Abugatas Julio , Castaneda Carlos , Gomez Henry 
Published: August 2019

Abstract
Background: The loss of function of gene p16(INK4a)/CDKN2 is associated with the development of several neoplasm and tumor progression, likewise, the level of tumor infiltrating lymphocytes is a predictive and prognostic biomarker of survival. This study aims to evaluate the association between composition of tumor infiltrating lymphocytes (TILs) and expression of p16 in acral lentiginous melanoma (ALM), and their impact on prognosis.
Materials and methods: A cohort of 148 surgical pathology specimens of ALM was studied. TILs were evaluated by immunohistochemical detection of CD3 and CD8, along with CD20, CD4, CD68, and CD163 in a subset of 43 cases, likewise, we classify the level of TILs in grades by combining density and distribution. p16 protein expression by immunohistochemistry was also investigated in all cases.
Results: The median age was 66 years, median Breslow thickness was 6.0 mm, Grade III of TILs was found in 28.4% and lymph nodes were involved in 44.6%. Breslow thickness (p&lt;0.001), stage I-II (p&lt;0.001), negative lymph nodes (p&lt;0.001) and &lt;10% p16 (p&lt;0.001) were associated with longer survival. Grade III of TILs was associated with thinner Breslow thickness (p=0.008) and lower mitosis (p=0.047). A higher density of CD3 TILs was associated with male gender (p=0.008), thinner Breslow thickness (p=0.047), negative lymph node (p=0.031), early stage (p=0.046), and p16 nuclear expression of &gt;10% (p=0.045). Higher CD8 TIL was associated with &gt;p16 (p=0.03). Survival analysis found that longer survival doesn’t associated with high grade of TILs (p=0.094). Levels of CD3+ and CD8+ cells were correlated with those of CD4+, CD20+, CD68+ and CD163+ immune cells.
Conclusions: Loss of expression of p16 is associated with lower levels of CD3+ and CD8+ TIL, indicating a probable relationship between p16 and TILs immune response in ALM.
Citation Format: Marco A. Galvez Nino, Miluska Castillo, Luis A. Bernabe, sandro Casavilca, Valeria Villegas, Joselyn Sanchez, Jorge Dunstan, Julio Abugatas, Carlos Castaneda, Henry Gomez. Tumor infiltrating lymphocytes are associated with p16 protein expression in acral lentiginous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4564.
Abstract 4573: Immune infiltrate profiling for progressive malignant stages of cutaneous squamous cell carcinoma
Authors: Alam Md Maksudul , Khandelwal Alok , Moore-Medlin Tara , Savage Hillary , Ma Xiaohui , Nathan Cherie-Ann 
Published: August 2019

Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer, affecting more than 300,000 individuals in the United States annually. Although, most cSCC can be treated successfully by surgery and/or radiation, a significant percentage of cSCC are aggressive and often unresectable and/or can metastasize to the lymph nodes. Organ transplant patients are at a significantly higher risk for cSCC due to a compromised immune system. Recently, the PD-1 inhibitor cemiplimab was approved for the treatment of patients with metastatic cSCC or patients with locally advanced cSCC who are not candidates for curative surgery or curative radiation. This suggests a critical role of immune cells in modulation of disease progression in cSCC. Hence, immune profiling of cSCC is important in identifying novel agents that could benefit patients. Our objective was to employ immunohistochemistry (IHC) to characterize the immune cell infiltrate in normal skin and compare it to actinic keratosis (AK), cSCC and metastatic cSCC (cSCC-M), in order to investigate the immune phenotype associated with progressive stages of malignancy. Our results suggest that AK, cSCC and cSCC-M exhibit significantly higher levels of CD3+, CD4+ and CD8+ T-cells compared to normal skin. Although, the number of CD3+ T-cells are comparable in AK, cSCC and cSCC-M, the CD8+ T-cells show higher infiltration in cSCC-M compared with cSCC and AK. The FOXP3+ Regulatory T-cells (T-reg) display higher abundance with progressive stages of carcinogenesis. However, surprisingly no significant alterations were observed in the abundance of CD4+ T-cells among AK, cSCC and cSCC-M. We also found that the CD68+ Tumor-associated macrophages (TAMs) exhibit a trend of increasing abundance with progressive disease stage. Our study suggests that the CD8+ T-cell population in cSCC-M could be potentially exhausted in the immune hostile tumor micro-environment (TME) constituted by T-reg and TAMs. Alternatively, CD8+ T-cells themselves might express FOXP3 and other immune suppressive factors, thereby reaching a state of anergy. Immunotherapy continues to be a burgeoning field and holds exciting therapeutic prospects in the treatment of cSCC. Moreover, transplant patients with aggressive cSCC are a unique patient population that could benefit from immunotherapy.
Citation Format: Md Maksudul Alam, Alok Khandelwal, Tara Moore-Medlin, Hillary Savage, Xiaohui Ma, Cherie-Ann Nathan. Immune infiltrate profiling for progressive malignant stages of cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4573.
Abstract 4574: Combining multimodal biomarkers as an immunogram to guide immunotherapy use: A proof of concept
Authors: Sbarrato Thomas , Sudre Lucie , Vanhille Laurent , Outters Pernelle , Angelova Mihaela , Mlecnik Bernhard , Vasaturo Angela , Bindea Gabriela , Fredriksen Tessa , Lafontaine Lucie , Bruni Daniela , Galon Jérôme , Fieschi Jacques 
Published: August 2019

Abstract
Our recent understanding of the immune contribution to fight cancer has deeply modified the standard of care of cancer patients. As an example, immunotherapies by immune checkpoint inhibitors (ICI) anti-PD1/PDL1 are now approved in several cancer indications, such as Non-Small Cell Lung Cancers or melanoma. However, ICI are less effective for other high incidence indications like colorectal cancer (CRC). Here, the heterogeneity as well as the relatively low degree of patient response to those immunotherapies have highlighted that factors, present in the tumor microenvironment (TME), may limit or boost the efficacy of treatment. In this context, the comprehensive assessment of these factors could be key to stratify patients and allow the selection of the optimal treatment.
In order to help clinical researchers and biopharmaceutical companies to measure the immune contribution to drug efficacy, HalioDx has developed the Cancer Immunogram, a solution based on Blank CU et al. Science (2016). Our multi-parameter approach encompassing a unique range of immune scoring assays is based on the analysis and the understanding of the immune contexture of tumors and offers a personalized and dynamic “fingerprint” of tumor-immune system interaction.
Here, we provide a Proof of Concept for the Cancer Immunogram in the context of CRC by combining the following technologies and biomarkers: Tumor Mutational Burden (Tumour foreignness), DNA mismatch-repair deficiency (MSI), TCR Sequencing (T Cell Clonality), Immunoscore® Colon (Immune Cell Infiltration), Immunosign® (Tumor Sensitivity to Immune Effectors), Halioseek® PDL1/CD8, Brightplex T-Cell Exhaustion Panel (Immune Checkpoints) and Brightplex MDSC Panel and Treg detection (Immune Suppression). We show that the Cancer Immunogram allows to identify patient specific patterns which might improve the prediction of the response to therapy. We believe that the Cancer Immunogram will help researchers and clinicians to personalise treatments in order to improve patients’ outcomes and response to cancer treatment.
Citation Format: Thomas Sbarrato, Lucie Sudre, Laurent Vanhille, Pernelle Outters, Mihaela Angelova, Bernhard Mlecnik, Angela Vasaturo, Gabriela Bindea, Tessa Fredriksen, Lucie Lafontaine, Daniela Bruni, Jérôme Galon, Jacques Fieschi. Combining multimodal biomarkers as an immunogram to guide immunotherapy use: A proof of concept [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4574.
Abstract 4578: Macrophages are important source of PD-L1 and PD-L1 expressing on central M2 macrophages leads to the poor prognosis of NSCLC patients: Via macrophage landscape analysis for NSCLC patients with tumor PD-L1 negative
Authors: Cao Lili , Che Xiaofang , Qu Xiujuan , Qiu Xueshan , Li Zhi , Yang Bowen , Wang Shuo , Liu Yunpeng 
Published: August 2019

Abstract
PD-1 antibody has achieved significant clinical efficacy for advanced non-small cell lung cancer (NSCLC), but the ORR is not optimistic for the non-selected patients. PD-L1,as the therapeutic target, is still controversial to be a predictor of efficacy.It was noticed that some patients with tumor cell PD-L1 negative could still benefit from anti-PD-1/PDL1 antibody therapy.Besides the tumor cells, PD-L1 was also known to express in immune cells in TME. Therefore, in this study, we aimed to clarify the factors that affect the PD-L1 expression in TME, and their functions on the NSCLC prognosis and the effect on anti-PD-1/PD-L1 therapy.With the multiple quantitative immunofluorescence staining on 94 tissue specimens of NSCLC patients with PD-L1 expressing negative on tumor cells, we surprisingly found that macrophages,especially M2 macrophages,were the main source of PD-L1 for patients with tumor cells PD-L1 negative.Futhermore, the expression of PD-L1 in central M2 macrophages(M2 macrophages that infiltrate into tumor islets),was important for the poor prognosis of NSCLC patients,suggesting that the expression of PD-L1 in macrophages may also be associated with the benefit of anti-PD-1 therapy, which is an important factor to be considered in evaluating the efficacy of immunotherapy in the future.
Note: This abstract was not presented at the meeting.
Citation Format: Lili Cao, Xiaofang Che, Xiujuan Qu, Xueshan Qiu, Zhi Li, Bowen Yang, Shuo Wang, Yunpeng Liu. Macrophages are important source of PD-L1 and PD-L1 expressing on central M2 macrophages leads to the poor prognosis of NSCLC patients: Via macrophage landscape analysis for NSCLC patients with tumor PD-L1 negative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4578.