bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4941: TTF1 negative in non small cell lung cancer adenocarcinoma: A prognostic factor
Authors: Cordoba Juan F. , Morales Serafin , Veas Joel , Rodriguez Alvaro , Reguart Noemi , Salud Antonieta 
Published: August 2019

Abstract
BACKGROUND: Patients with thyroid transcription factor 1 (TTF1) negative lung adenocarcinoma (ADC) have been reported to have a worse prognosis and to lack epidermal growth factor receptor (EGFR) mutations. This study describes a series of sample tumors from patients with clinically confirmed lung cancer.
METHODS: In all lung cancer patients diagnosed in the University Hospital of Lleida from January 2011 to December 2016, a real world data study of TTF1-negative ADC was performed, using TTF1 clone 8G7G3/1(DAKO®). Each patient’s clinical history, pathology specimens and molecular results were noted. Two hundred and thirty one patients with TTF1 positive lung ADC formed the control group.
RESULTS: Twenty seven (27) patients were identified with ADC TTF1 negative (74% males). The media age was 66 years. The smoking history was as follows: 55,5% former, 29,6% ex smokers and 14,8% never smokers. The clinical stages were as follows: stage I or II (n = 3 [11%]), stage III (n = 4 [14,8%]) and stage IV (n = 20 [74%]). Patients’ mean survival was 7,6 vs 24,4 months in ADC TTF1 negative patients (P= 0,00001). Three hundred and thirty four (334) patients with ADC were found, TTF1 results were available in 258 (77,2%) cases, of them twenty-seven cases (10,4%) had TTF1 negative; when they were compared with the control group, TTF1 negative patients had overall shorter survival (P= 0,00001), regardless of whether patients were treated with radical or palliative intent: 34,4 vs 10, months P=0,00001 (radical treatment) and 14,6 vs 6,7 months P= 0,007 (palliative intent). EGFR mutations were less frequent (P= 0,046) in TTF-negative tumors 5,5% vs 25,3%.
CONCLUSIONS: Patients with TTF1 negative NSCLC ADC, have worse overall survival regardless of treatment intention and a lower frequency of EGFR mutations.
KEYWORDS: lung adenocarcinoma (ADC), non small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), prognosis in thyroid transcription factor 1 negative (TTF1) adenocarcinoma.
Citation Format: Juan F. Cordoba, Serafin Morales, Joel Veas, Alvaro Rodriguez, Noemi Reguart, Antonieta Salud. TTF1 negative in non small cell lung cancer adenocarcinoma: A prognostic factor [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 4941.
Abstract 4947: Plucked anagen scalp hair: A comparison between different analytical techniques to establish reproducible drug induced transcriptional changes and provide pharmacodynamic biomarker and target engagement information from oncology patients
Authors: Mefo Tim , Harrison Elliott , Murdoch Alan , Reed Benjamin 
Published: August 2019

Abstract
Plucked anagen scalp hair is an ideal surrogate tissue to monitor drug induced transcriptional changes. High vascularisation of the hair follicle, ease of sampling and high degree of similarity of expression in hair of pathways dysregulated in cancers, make the cellular bulb of plucked human scalp hair an excellent surrogate tissue for the non-invasive monitoring of pharmacodynamic (PD) and mechanism of action (MOA) effects in clinical trials. Using our ex vivo plucked hair culture platform, plucked scalp hair bulbs from several healthy donors were exposed to BEZ235, a dual pan-class PI3K and mTOR inhibitor at different concentrations and durations. Total RNA was isolated from the cellular bulb of anagen hair post-culture and samples were assessed by microarray and RNA-seq analysis to assess dose dependent global transcriptional alterations and develop a gene expression signature indicative of BEZ235 exposure. Two different microarrays, the Affymetrix Clariom D and U133 plus 2.0 arrays, were directly compared to RNA-seq data obtained from the same ex vivo culture samples. Genetic signatures indicative of exposure of plucked scalp hair to BEZ235 were established using all three analytical techniques. The transcriptional readouts from the plucked scalp hair samples revealed strong correlations (0.97-0.99) in the genes expressed in anagen scalp hair between donors. In addition, global gene expression data indicated that assessing pooled scalp hairs was sufficient to detect significant differential expression (p&lt;0.05 & 1.5 fold change) underpinning the low variance in the majority of target genes in plucked hair as a biomarker platform. Gene signatures for compounds targeting the PI3K/mTOR pathway that were established using the ex vivo plucked scalp hair platform were subsequently used to support clinical trials and scalp hair taken from patients receiving treatment showed an excellent post-exposure target signature modulation. In summary, the results of the ex vivo plucked assessment generated a dose dependent and biologically relevant transcriptional signature following exposure to BEZ235. Plucked anagen scalp hair is therefore an ideal non-invasive surrogate tissue to obtain drug-induced pharmacodynamic biomarker and target engagement information from oncology patients.
Citation Format: Tim Mefo, Elliott Harrison, Alan Murdoch, Benjamin Reed. Plucked anagen scalp hair: A comparison between different analytical techniques to establish reproducible drug induced transcriptional changes and provide pharmacodynamic biomarker and target engagement information from oncology patients [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 4947.
Abstract 4963: A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment
Authors: Kiefel Helena , Haria Dhwani , Katlinskaya Yuliya , Ravichandar Divya , McLaughlin Lily , Jain Sunit , Weinmaier Thomas , Iwai Shoko , DeSantis Todd , Takeuchi Toshi , Dabbagh Karim , Graham Kareem 
Published: August 2019

Abstract
The composition of the gut microbiota affects cancer development, progression, and response to therapy. A number of commensal bacteria, including Bifidobacterium, have been associated with increased response to immune checkpoint inhibitors in mouse tumor models and in cancer patients.
We hypothesized that secreted peptides or proteins are driving the Bifidobacterium-mediated effects. Using our unique bioinformatic-driven discovery platform we nominated putatively secreted Bifidobacterium-derived peptides for evaluation in immune cell effector assays. We demonstrate that several of the peptides induce secretion of pro-inflammatory cytokines (e.g., IL-6, TNF) by in vitro-generated mouse and human dendritic cells, as well as effector cytokine secretion (e.g., IFNγ, IL-2) by mouse splenic T lymphocytes in vitro.
To investigate the function of Bifidobacterium-derived peptides in the context of the tumor microenvironment we injected the candidate peptide SG-A directly into the tumor of CT26 tumor-bearing mice and analyzed the immune phenotype using the Nanostring PanCancer Immune Profiling panel and flow cytometry. Both Nanostring as well as flow cytometry analysis showed an increase in CD45+ tumor-infiltrating lymphocytes in SG-A treated tumors. SG-A peptide also induced the upregulation of dendritic cell function genes (CD40, CD83, and CD86) and multiple effector cytokines and chemokines. Re-stimulation of tumor-draining lymph node cells with AH1 peptide (a CT26 tumor-derived antigen) also increased induction of IFNγ in SG-A treated animals (vs. vehicle-treated controls).
Collectively, our results demonstrate the utility of the Second Genome discovery platform for leveraging microbiome science to identify novel immunoregulatory factors. This platform offers a promising approach to identify agents with potential for use as therapeutics in cancer immunotherapy.
Citation Format: Helena Kiefel, Dhwani Haria, Yuliya Katlinskaya, Divya Ravichandar, Lily McLaughlin, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment [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 4963.
Abstract 4966: Characteristics of immune repertoires in early lung cancer patients
Authors: Wang Jin , Hu Xihao , Zhang Peng , Liu Xiaole Shirley 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer death in the world, and early lung cancer detection is vital for improving the overall survival. Besides x-ray and CT scan, few genetic tests have been widely used for detecting early lung tumors. We hypothesize that early lung cancer patients have some unique features in the immune repertoires which can be utilized for early cancer detection and profiling disease development. In this study, we performed RNA-seq for paired tumor and tumor-adjacent normal samples from 59 early lung adenocarcinoma patients. We found that early lung tumors have more cytokine activities, higher B cell and CD4+ T cell infiltration, and lower CD8+ T cell infiltration compared to normal lung tissues. We assembled B cell receptors from RNA-seq reads and found more B cell clonal expansion and somatic hypermutations in the tumor than in tumor-adjacent normal tissues, similar to the B cell repertoires in late-stage lung cancer patients. In both early- and late-stage lung tumors, we identified a few cytokines that positively correlated with more IgA isotypes and associated with patient survival. To gain more insights on the B cell binding specificity, we performed motif enrichment analysis for paired tumor and normal samples and validated some tumor-enriched receptor motifs in matched patient blood samples, which implies a new way of early cancer detection. More interesting, we assembled microbial transcripts from RNA-seq data and identified some known lung disease-related species in both tumor and normal samples. The complex interactions between cancer cells, B cells, and microbiota in the early lung tumor development are waiting to be elucidated.
Citation Format: Jin Wang, Xihao Hu, Peng Zhang, Xiaole Shirley Liu. Characteristics of immune repertoires in early lung cancer patients [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 4966.
Abstract 4974: Germline prognostic SNPs and tumor-immunity-specific expression QTL (tis-eQTL) in cancer
Authors: Yu Xiaoqing , Wang Xuefeng 
Published: August 2019

Abstract
Introduction: Immunotherapy has produced promising results in treating cancers. Recent studies that aim to predict which patients can benefit from an immune checkpoint blocker have been largely focused on tumor molecular profiling such as tumor mutation burden and T cell infiltrations. However, whether the immunity landscape in tumor can be favorably or adversely affected by polymorphisms carried in the germline remains unknown and understudied.
Methods: Here we conduct the largest investigation of tumor-immunity-specific expression QTL to date, or tis-eQTL, to systematically identify germline genetic variants that affect immune landscape in tumor. We develop a reliable statistical method for tis-eQTL mapping using RNA-seq data from heterogeneous tumor samples. We analyze genomic data from 10,380 cancer patients from 33 cancer types to reveal interactions between genetic variants (derived from germline SNP array and WES data) and immune- phenotypes derived from tumor RNAseq data. These phenotypes include immune gene expression (such as CD3E, GZMA, CXCR3 and PRF1), T-cell receptor (TCR) clonality, and antigen presenting scores (APM).
Results: We observed that stratifying patients by the prioritized pathogenic germline polymorphisms exposed distinct tumor immune landscape, implicating new prognostic factors or risk genes of cancer. We further prioritize SNPs that fulfill two criteria: (a) with differential overall survival (b) have a differential expression pattern in immunogenic signatures. In support of these findings, we show that the top-ranked SNPs are associated with treatment responses to anti-PD-1 therapy in melanoma and non-small cell lung cancer. This study creates a unique and pioneering resource of prognostic germline variants with the potential to modulate immune therapy response and cancer risk, opening new avenues for developing next generation therapeutics and for personalizing risk assessment.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaoqing Yu, Xuefeng Wang. Germline prognostic SNPs and tumor-immunity-specific expression QTL (tis-eQTL) in 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 4974.
Abstract 4975: Using humanized B-hSIRPa/hCD47 mouse model to evaluate the efficacy and toxicity of CD47 and SIRPa antibodies
Authors: Li Yanan , Guo Chaoshe , Xiang Jie , Lin Qingcong 
Published: August 2019

Abstract
Cancer immunotherapy is one of the most promising research areas in the field of cancer therapy. Along the IO drug development process, production of mouse models for in vivo efficacy evaluation has always been a rate-limiting step. Therefore, we generated a novel humanized knock-in mouse to evaluate the efficacy of human IO antibodies.
CD47 is a transmembrane protein expressed in many human tissues. SIRPa, which is expressed on phagocytic cells, was identified as the receptor of CD47. Engagement of SIRPa by CD47 serves as “do not eat me” signal, inhibiting the phagocytic activity of macrophages. Antibodies interfering with the CD47-SIRPa interaction block inhibition and promote tumor destruction. While CD47 is a potential target for antibody development, side effects associated with CD47 blockade have emerged as a major concern, especially anemia.
To evaluate the efficacy and toxicity of CD47 antibody, we generated a double humanized B-hSIRPa/hCD47 mouse. In this model, exon2 in mouse SIRPa and CD47 were replaced with the corresponding human sequences. In homozygous mice, mouse SIRPa and CD47 was absent and only human protein expression was detected, B-hSIRPa/hCD47 mice paired with genetically modified MC38-hCD47 cancer cells were used to screen CD47 antibodies by balancing their efficacy and toxicity. Antibodies with less toxicity exhibited minimal weight loss, minimal effects on blood cell and platelet production, and reduced ALT/AST elevation in mice. Thus, we demonstrated that these humanized mice could expedite and improve the development of safer CD47 antibodies.
Humanized B-hSIRPa/hCD47 mice can also be used to evaluate the efficacy of antibodies targeting SIRPa. We also generated triple humanized B-hPD-1/hSIRPa/hCD47 and B-hPD-L1/hSIRPa/hCD47 mice that would be useful to develop combination therapies of PD-1/PD-L1 and SIRPa/CD47 antibodies. Humanized B-hSIRPa/hCD47 mice are a promising in vivo efficacy model for the development of CD47 and SIRPa antibodies that can be advanced to human clinical trials.
Citation Format: Yanan Li, Chaoshe Guo, Jie Xiang, Qingcong Lin. Using humanized B-hSIRPa/hCD47 mouse model to evaluate the efficacy and toxicity of CD47 and SIRPa antibodies [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 4975.
Abstract 498: Integrating bulk and spatial profiling technologies for the discovery of RNA and protein biomarkers in muscle invasive bladder cancer
Authors: Zhang Zhaojie , Das Subhasree , Korpal Manav , Kumar Pavan , Gong Jingjing , Liang Yan , Hoang Margaret , Beecham Joseph , Rimkunas Victoria 
Published: August 2019

Abstract
Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting the existence of complementary immune evasion mechanisms underscoring the need for comprehensive immune profiling of patient tumor samples. The PPARγ pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Immune cell-infiltration is controlled by activated PPARγ, which in turn inhibits expression/secretion of inflammatory cytokines. Clinical data sets indicate that PPARγHigh impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies.
Here, we report a comprehensive biomarker study aimed at identifying a single, highly multiplexed platform for profiling the tumor microenvironment in clinical-type specimens as formalin-fixed, paraffin-embedded (FFPE) samples. A cohort of PPARγHigh and PPARγLow muscle invasive bladder cancer samples were used for the technology assessments. Gene expression patterns were measured using a combination of research use only genomics and spatial genomic technologies to determine concordance including RNA-seq, spatial in situ hybridization (GeoMx™ Digital Spatial Profiler) and IO360. We determined that multiple RNA and protein-based technologies were able to accurately characterize the immune phenotypes of PPARγHigh tumors. However, the GeoMx™ technology was ideal for precious samples since it digitally quantifies target abundance while maintaining spatial resolution in only two FFPE slides.
GeoMxTM DSP technology is for Research Use Only and not for use in diagnostic procedures.
Citation Format: Zhaojie Zhang, Subhasree Das, Manav Korpal, Pavan Kumar, Jingjing Gong, Yan Liang, Margaret Hoang, Joseph Beecham, Victoria Rimkunas. Integrating bulk and spatial profiling technologies for the discovery of RNA and protein biomarkers in muscle invasive bladder 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 498.
Abstract 4988: CD 137 agonists as an adjunct to immune checkpoint inhibitors to overcome resistance in melanoma
Authors: Danturti Sreedevi , Mayer Lena , Victor Christina Twyman Saint 
Published: August 2019

Abstract
Background: Melanoma is currently the fifth most common cancer in men and sixth most common in women with an estimate of 9,320 deaths from the disease in the United States. Anti-PD1, an immune checkpoint inhibitor, is FDA approved to treat metastatic melanoma with durable responses observed in 53% of patients. Studies suggest that combining therapies (e.g. immune checkpoint inhibitors, radiation therapy, and/or agonist antibodies) can be more effective than monotherapy. CD137 is expressed on a variety of cell populations including T cells, dendritic cells (DCs) and macrophages. CD137 agonists have proved effective in multiple murine tumor models and have had modest responses in early clinical trials. We hypothesize that CD137 agonists can augment the anti-PD1 anti-tumor immune response resulting in improved overall survival and decreased tumor burden in melanoma.
Methods: 499 melanoma cells, which were derived from B16-F10, are implanted on both flanks of C57BL6 mice. The mice are treated with anti-CD137 and/or anti-PD1 on day 10, 13 and 16 post-implantation. The anti-tumor response is assessed by both overall survival and tumor burden. Tumors are harvested on day 19 for protein, transcriptomic and immune profiling.
Results: Monotherapy with either anti-CD137 agonists or anti-PD1 antagonists increases the overall survival by 8 days; whereas, combination therapy results in an increase of 25 days. To investigate the mechanisms of response and resistance to combination therapy, tumors were harvested and assessed via a proteomic array that identified 36 proteins that were upregulated in the non-responders. Transcriptomic profiling of these tumors using Nanostring IO 360 corroborated these findings and identified both the myeloid the T cell immune populations are upregulated in responders.
Conclusions: These results suggest a dual role for both the innate and adaptive immune response in treating melanoma. By understanding the mechanism of response and further characterization we can further best apply the combination therapy to overcome resistance after immunotherapy.
Note: This abstract was not presented at the meeting.
Citation Format: Sreedevi Danturti, Lena Mayer, Christina Twyman Saint Victor. CD 137 agonists as an adjunct to immune checkpoint inhibitors to overcome resistance in 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 4988.
Abstract 5020: Therapeutic potential of an immune modulatory CCL22-based vaccine
Authors: Lecoq Inés , Kopp Katharina L. , Christensen Rikke , Pedersen Ayako W. , Martinenaite Evelina , Zocca Mai-Britt , Andersen Mads H. 
Published: August 2019

Abstract
CCL22 is a macrophage-derived chemokine that exerts immunosuppressive functions by the recruitment of regulatory T cells (Tregs) through the CCL22/CCR4 axis. It is expressed by cells in the tumor microenvironment (TME) in many different cancer tissues including breast, lung, and pancreatic cancer and is thought to promote the suppression of anti-cancer immunity. Recently, we described that CCL22-specific T-cells from cancer patients can kill CCL22-expressing tumor cells, and activation of CCL22-specific T cells may directly influence the CCL22 concentration in the TME, suggesting that CCL22 may be an interesting target for an immune modulatory vaccine.
Thus, in the present study we have targeted CCL22-expressing cells by activation of CCL22-specific effector T cells by peptide vaccination in tumor models. We present here that CCL22-targeting peptide vaccination leads to expansion of predominantly CD8+, IFNγ-secreting CCL22-specific T cells in both BALB/c and C57BL/6 mice. Furthermore, CCL22 vaccination results in delayed tumor growth and enhanced survival in tumor harboring hosts in CT26 and Pan02 models. Preliminary assessment of gene expression in the tumors reveals that CCL22 vaccination leads to a reduction of CCL22 expression, alongside other immune suppressive molecules, such as IDO1 in the TME. Characterization of vaccine-mediated changes of cellular composition of the TME is currently ongoing.
In conclusion, our findings provide a rationale for a novel cancer immunotherapy to target the immune suppressive TME.
Citation Format: Inés Lecoq, Katharina L. Kopp, Rikke Christensen, Ayako W. Pedersen, Evelina Martinenaite, Mai-Britt Zocca, Mads H. Andersen. Therapeutic potential of an immune modulatory CCL22-based vaccine [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 5020.