bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B11: Low-dose HMGN1 synergistically enhances antitumor immunity in CD4 depleting antibody-treated mice
Authors: Chen Chang-Yu , Ueha Satoshi , Yokochi Shoji , Ishiwata Yoshiro , Ogiwara Haru , Deshimaru Shungo , Matsushima Kouji 
Published: February 2019

Abstract
Anti-CD4 antibody treatment increases the number of and activates tumor-specific CD8+ T cells by depleting immunosuppressive cell populations (such as CD4+Foxp3+ T cells), thus suppressing tumor growth in mice [Ueha et al, Cancer Immunol Res, 3:631 (2015)]. Co-administration of anti-CD4 antibody with other immune stimulators can further augments its anti-tumor efficacy. Here, we co-administered an alarmin, high mobility group nucleosome binding protein 1 (HMGN1), with an anti-CD4 antibody. In the Colon26 subcutaneous tumor model, anti-CD4 antibody with low-dose HMGN1 (&lt; 0.2 g/mouse, i.p.) synergistically suppressed tumor growth comparing to untreated and single-treated controls (p&lt; 0.001). In mice receiving the combination treatment, CCR7+ migratory dendritic cells (mDCs) expressed higher level of co-stimulatory receptors (CD80 and CD86), and the number of CCR7+ mDCs and CD8+CD137+PD-1+ T cells further increased in the tumor. Collectively, these results suggest that low-dose HMGN1 may mobilize and activate the CCR7+ migratory DCs and tumor specific CD8+ T cells in the tumor. Combination therapy with low-dose HMGN1 and CD4 depleting antibody represents a new strategy to treat solid tumors.
Citation Format: Chang-Yu Chen, Satoshi Ueha, Shoji Yokochi, Yoshiro Ishiwata, Haru Ogiwara, Shungo Deshimaru, Kouji Matsushima. Low-dose HMGN1 synergistically enhances antitumor immunity in CD4 depleting antibody-treated mice [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B11.
Abstract B15: Combination immunotherapy of murine prostate cancer using a Listeria-based PSA vaccine: Immune correlates of efficacy and resistance development
Authors: Bongiorno Emily K. , Baybutt Trevor , Portocarrero Carla , Snook Adam , Dicker Adam P. , Hayes Sandra M. , Rodeck Ulrich 
Published: February 2019

Abstract
Combining immunotherapy and radiation has emerged as a promising strategy to boost efficacy of diverse immunotherapeutic agents including tumor vaccines. Immuno-radiotherapy uses radiation to increase antigen exposure and, potentially, to amplify and broaden immune responses triggered by tumor vaccines or checkpoint inhibitors. Here we explored the therapeutic potential of combining radiation therapy (RT) and a prostate cancer vaccine (ADXS-PSA) currently in clinical development. ADXS-PSA is a live-attenuated Listeria monocytogenes (Lm)-based vector expressing human PSA (Haas et al., J Immunother Cancer 2015:3(Suppl.2):P153). We confirm and extend earlier observations (Hannan et al., Can Immunol Immunother 61:2227) that the two treatment modalities cooperatively induce regression of syngeneic prostate cancer cells expressing human PSA (TPSA23). The extent of tumor growth inhibition depended on temporal sequencing of vaccine and RT with concurrent administration being superior to other treatment schedules. Using the optimal sequencing protocol, tumors were collected during (day 20) and after treatment (day 38) post-implantation to assess immune infiltrates and function during initial tumor regression and upon resumption of tumor growth. Tumor regression by the RT/vaccine combination was associated with enhanced T cell activation and robust IFNγ signatures in the tumor microenvironment as determined by transcriptome analyses. TCRβ chain sequencing revealed elevated and sustained T cell diversity in tumor tissue of mice receiving the RT/vaccine combination. Transcriptome analysis further revealed that sustained T cell diversity in the RT/vaccine group was accompanied by higher expression levels of resident and/or memory phenotypic markers. Finally, molecular analysis of recurring tumors revealed induction of select immune checkpoints (including PD-L1 and CD137) as a function of treatment, establishing a rationale to test whether therapeutic efficacy can be boosted further by targeting these markers. The results obtained support combining ADXS-PSA with radiation in the clinic and provide a versatile experimental platform to optimize combination immunotherapeutic strategies.
Citation Format: Emily K. Bongiorno, Trevor Baybutt, Carla Portocarrero, Adam Snook, Adam P. Dicker, Sandra M. Hayes, Ulrich Rodeck. Combination immunotherapy of murine prostate cancer using a Listeria-based PSA vaccine: Immune correlates of efficacy and resistance development [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B15.
Abstract B22: Lymphocytes inhibits the tumor metastasis in 4D cellular lung model by reducing the number of live CTCs in circulation
Authors: Mishra Dhruva Kumar , Miller Ross A. , Kim Min P. 
Published: February 2019

Abstract
Objective: Mouse lung cancer cell lines 393P and 344SQ are derived from KrasLA1/+ p53R172HΔG mice and have different metastatic potential in immunocompetent mice. 393P cells have local primary tumor growth but do not form metastatic lesions while344SQ cells form a primary tumor and metastatic lesions when injected into the subcutaneous space of 129 sv mice. We postulated that the presence of lymphocytes led to differential phenotype for these two cells. In order to test this hypothesis, we used novel cellular 4D ex vivo lung cancer metastasis model created using rat lung where we can determine the impact of lymphocytes on number of circulating tumor cells and formation of metastatic lesions.
Methods: We grew GFP tagged 393p or 344SQ mice cells on cellular 4D lung model as control group and for treatment group we added activated lymphocytes on day 0, day 3 and day 5. These activated lymphocytes were obtained by harvesting spleen from mice injected with 393p and 344SQ (1Million) in 129Sv mice. Cellular model with GFP tagged CTCs were counted on day 6 and day 11 by Flow sorting instrument. Primary tumor was removed on day 7 and metastatic lesions were allowed to grow till day 14. Tissues were processed for H&E and Immunohistochemistry and the pathologist determined the amount of tumor cells on the slides.
Results: Primary tumor was well formed on cellular lung model by both 393p and 344SQ cells with peribronchiolar distribution. Lung matrix was intact in untreated as well as lymphocyte treated cellular models and tumor histology was more like non-small cell lung cancer. Lymphocyte treatment significantly reduces the presence of CTCs in circulation from 393p growing lung models (35172 vs 10592; p=0.02) while no effect was found on CTCs from 344SQ growing models (13841 vs 7072; p=0.27). Furthermore, there were significantly less metastatic lesions formed with 393p growing cellular model in the presence of lymphocytes (p=0.008), while there was no impact of lymphocytes on formation of metastatic lesion with 344SQ.
Conclusion: Lymphocytes inhibit metastatic lesion formation in 393P cell lines but not 344SQ cell lines in cellular lung model. The cellular 4D lung recapitulates the phenomenon exhibited by in vivo in presence of activated lymphocytes. The model can be used to study the role of different components of a tumor’s microenvironment in tumor metastasis.
Citation Format: Dhruva Kumar Mishra, Ross A. Miller, Min P. Kim. Lymphocytes inhibits the tumor metastasis in 4D cellular lung model by reducing the number of live CTCs in circulation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B22.
Abstract B26: Genomic analysis of the virus-induced tumor microenvironment in six cancer types
Authors: Varn Frederick S. , Li Dawei , Cheng Chao 
Published: February 2019

Abstract
With the growing successes of immunotherapy, there is now a focus on identifying biomarkers that can predict response and long-term survival following treatment. The presence of immunogenic antigen proteins has been linked to improved response rates across patients receiving immune checkpoint inhibitors. However, these findings have been localized to melanoma and lung tumors which contain high mutation burdens and thus higher neoantigen loads. Viruses cause approximately 20% of all human cancers and are especially prevalent in head and neck cancers, cervical cancers, and liver cancers. Viral protein expression is another source of immunogenicity, making these tumor types potent targets for immune checkpoint inhibitors. Recent advances in genome-based immune profiling technologies have enabled the systematic characterization of the tumor microenvironment over large cohorts of patients. In this study, we apply several of these tools to The Cancer Genome Atlas and other datasets to define how virus infection shapes the tumor microenvironment of 6 virus-associated tumor types. Across all tissues studied, the cellular composition of the tumor microenvironment varied between tumors based on viral status, with infected tumors often exhibiting increased infiltration of cytolytic cell types. A gene expression signature capturing these virus-induced changes in the tumor microenvironment successfully predicted virus status in independent datasets and was associated with improved prognosis in head and neck cancer, indicating a protective role for virus-induced immune infiltration. To examine how viral gene expression affects the infiltrating T cell repertoire, T cell receptor diversity and abundance comparisons were made between viral and non-viral samples. The analyses presented here suggest virus infection is associated with a robust immune response. These findings have implications for precision medicine approaches to tumor immunotherapy.
Citation Format: Frederick S. Varn, Dawei Li, Chao Cheng. Genomic analysis of the virus-induced tumor microenvironment in six cancer types [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B26.
Abstract B30: Digital multiplex immunofluorescence analysis identifies immune profiles in the tumor stroma associated with clinical outcome
Authors: Mezheyeuski Artur , Bergsland Christian , Backman Max , Sjöblom Tobias , Lothe Ragnhild A. , Bruun Jarle , Micke Patrick 
Published: February 2019

Abstract
Background: The recent successes of immunotherapy in non-small cell lung cancer (NSCLC) raise the interest to the deeper understanding of the diversity of the immune microenvironment. Meticulous characterization of the immune cell infiltrates is crucial for patients’ prognosis and the prediction therapeutic effects. The aim of this study was to analyze expression profiles of the immune cells and their linkage to clinical parameters in NSCLC patients.
Methods: A tissue microarray of the NSCLC cohort comprised of 55 cases was used in the study. The staining was performed with the antibodies against CD8, CD20, CD4, FoxP3, CD45RO and pan-cytokeratin together with immuno-fluorescent markers (Opal, Perkin Elmer) and digital images acquired by a multispectral imaging system (Vectra 3, PerkinElmer). Marker expression pattern was evaluated on a cell level in total sample area, or in stroma and tumor area separately. Conventional immunohistochemical techniques and RNAseq data were used to validate the method.
Results: Marker expression intensities were used to identify 5 non-epithelial cell classes, which express CD8, CD20, CD4, FoxP3, CD45RO. Relative abundance of marker-positive cells in individual cases were subjected to hierarchical clustering analysis, for the discovery of distinct immune cell infiltration patterns. The resulted clusters were exploratively analyzed with regard to survival associations. Patients with specific immune profile with high infiltration of FoxP3+ cells, moderate infiltration of CD4+ and CD8+ cells and low quantity of CD20+ and CD45RO+ cells in the stroma were associated with longer survival (median 87 vs. 54 month, log-rank p=0.050).
Conclusion: Multi-marker analysis on single-cell levels with the fluorescence multiplexed IHC technique provides a valuable basic immune profile of cancer patients. Clustering analysis of the expression of immune markers identified a group of patients with improved survival in NSCLC independent of histology.
Note: This abstract was not presented at the conference.
Citation Format: Artur Mezheyeuski, Christian Bergsland, Max Backman, Tobias Sjöblom, Ragnhild A. Lothe, Jarle Bruun, Patrick Micke. Digital multiplex immunofluorescence analysis identifies immune profiles in the tumor stroma associated with clinical outcome [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B30.
Abstract B82: Identification of tumor neoantigens for combination therapy in murine tumor models
Authors: Lee Karin L. , Nguyen Andrew T. , Benz Steven C. , Rabizadeh Shahrooz , Hodge James W. , Palena Claudia , Schlom Jeffrey , Hamilton Duane H. 
Published: February 2019

Abstract
The adoption of anti-CTLA-4 and anti-PD-1/PD-L1 blockade has dramatically changed the treatment approaches in multiple cancer types, and has demonstrated the power of the immune system to control the outgrowth of neoplastic lesions. Accumulating evidence suggests these successes are mediated by T cells targeting nonsynonymous mutations unique to the patient’s tumor. When used in combination with checkpoint inhibition, or other standard of care treatment modalities, vaccines targeting tumor neoantigens have the potential to greatly enhance patient survival. Recent advances in DNA/RNA sequencing and bioinformatic analysis have made it possible to rapidly identify nonsynonymous mutations being expressed in patient tumors. As the number of nonsynonymous mutations detected in patient samples can range from less than 10 to several thousand, it is necessary to develop strategies to identify and rank neoantigens with a greater probability of being immunogenic and mediating regression of established tumors.
In the present study, we harvested tumors from mice bearing syngeneic tumors, and performed DNA/RNA sequencing to identify nonsynonymous mutations to use as tumor specific neoantigens. These potential neoantigens were ranked based upon their proposed in-silico MHC binding affinity, and the relative abundance of each transcript as determined by RNA-seq. Top ranking 9-mer neoantigens peptides were synthesized and evaluated. We assessed neoantigens for their ability to bind MHC in vitro, and expand antigen-specific T cells in vivo.
To further augment the immunogenicity of our neoantigen 9-mer peptides, we used them in combination with an IL-15 super-agonist (ALT-803) and an anti-PD-L1 antibody. When used in combination with these immune-modulators, we observed a dramatic increase in the magnitude of the immune response generated against our neoantigens, which associated with increased tumor therapy. This study provides the rational for the combination of neoantigen vaccines with immune modulators to slow tumor growth and extend survival.
Citation Format: Karin L. Lee, Andrew T. Nguyen, Steven C. Benz, Shahrooz Rabizadeh, James W. Hodge, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. Identification of tumor neoantigens for combination therapy in murine tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B82.
Abstract B83: Intratumoral T cell receptor β repertoire as a biomarker in head and neck squamous cell carcinoma
Authors: McGrath Lara , Maloney Elizabeth , Secrier Maria , Angell Helen , Jones Emma , Dougherty Brian , Stetson Daniel , McCoon Patricia , Pierce Andrew , Barker Craig , Barrett Carl 
Published: February 2019

Abstract
In this study, we examine the T cell receptor (TCR) repertoire in a cohort of Head and Neck Squamous Cell Carcinoma (HNSCC) patients (n=50) at time of diagnosis. The TCR repertoire is indicative of the ability of the body to mount an immune response, with increased productive clonality within the tumor environment suggesting accumulation of tumor antigen specific T cells. Recent studies demonstrate that the intratumoral TCR repertoire is prognostic of response to anti-PD-1 (Tumeh et al., 2014) and anti-CTLA-4 (Page et al., 2016) therapies. Here we examine diversity and clonality of intratumoral T cell β repertoires in HNSCC patients independently and in conjunction with other biomarkers including tumor mutational burden/neoantigen load, expression of inhibitory checkpoints, and characterization of immune cell populations, as well as clinical metadata including HPV status, smoking history, and survival outcomes. The TCRβ repertoire was analyzed from FFPE primary tumor samples through targeted next generation DNA sequencing of the TCRβ loci and examination of the CDR3 sequences to determine clonality of the TCRβ repertoire (1 – Pielou’s evenness). Somatic genomic alterations, tumor mutational burden, and HLA typing were conducted through whole exome sequencing. Inhibitory checkpoint expression and characterization of immune cell populations were conducted through immunohistochemistry, RNA expression, or both methods. Preliminary results indicate productive clonality of the TCR repertoire in the range of 0.03-0.16. In examining HPV+ and HPV- patients, where we hypothesize the presentation of foreign peptides of viral etiology will produce an increase in T cell populations recognizing those neoantigens, we see no difference in either T cell infiltration or productive clonality. However, we observe that PD-L1 status is significantly correlated (p &lt; 0.05) to productive clonality of the tumor infiltrating T cells, with a higher average productive clonality in PD-L1+ patients. Ongoing studies will characterize the landscape of somatic genomic alterations including tumor mutational burden, and gene expression profiles of the tumor microenvironment.
Citation Format: Lara McGrath, Elizabeth Maloney, Maria Secrier, Helen Angell, Emma Jones, Brian Dougherty, Daniel Stetson, Patricia McCoon, Andrew Pierce, Craig Barker, Carl Barrett. Intratumoral T cell receptor β repertoire as a biomarker in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B83.
Abstract B86: Circulating cytokines, chemokines, and small molecules follow distinct expression patterns in acute myeloid leukemia
Authors: Islam Mirazul , Mohamed Elsa Haniffah , Esa Ezalia , Kamaluddin Nor Rizan , Zain Shamsul Mohd , Yusoff Yuslina , Assenov Yassen , Mohamed Zahurin , Zakaria Zubaidah 
Published: February 2019

Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with a complex interplay of genetic and/or cytogenetic alterations in hematopoietic progenitors, together with aberrant cytokines, chemokines, and small molecules (analytes) expression in the tumor microenvironment, contribute to AML pathogenesis. Although deregulated analytes are well documented in AML, their co-expression patterns are not yet identified. The baseline of circulating analytes in AML is found to be significantly variable between studies. Also, plasma baselines for some analytes that are biomarkers for other cancers have not been previously reported in AML. We hypothesized that comprehensive profiling of plasma analytes would provide greater insight of baselines variability and co-expression signature compared with individual analyses, potentially leading to the identification of novel diagnostic biomarkers and therapeutic targets in AML. Two sets of analytes were selected for this study: (i) 22 reported-analytes (baselines have been previously reported in AML) and (ii) 10 novel-analytes (baselines have not been previously reported in AML). We used multiplex array technology to simultaneously detect and quantify 32 plasma analytes levels in 38 patients (cases= 19, controls=19). We observed that baseline expression ranges are higher for three analytes (FGF2, MPO, and sFas) and lower for two analytes (SCF and sFasL) compared to previously published reports. In our study, 16 analytes are found to be significantly deregulated (13 higher, 3 lower, Mann-Whitney U-test, p-value &lt;0.005) where 5 of them have never been reported before in AML. We predicted a 7-analytes containing multiplex panel (Cathepsin D, Ferritin, MIF, Galectin-3, HGF, MPO, and IL8) for diagnosis of AML, among them, MIF could be a possible therapeutic target. In addition, we observed that circulating analytes show co-expression signatures, that lead us to speculate that expression signatures have the potential to be used for subclassification of AML, complementing cytogenetic, genetic, and epigenetic information. In conclusion, circulating analytes expression in AML differs from normal, and follow distinct expression patterns.
Note: This abstract was not presented at the conference.
Citation Format: Mirazul Islam, Elsa Haniffah Mohamed, Ezalia Esa, Nor Rizan Kamaluddin, Shamsul Mohd Zain, Yuslina Yusoff, Yassen Assenov, Zahurin Mohamed, Zubaidah Zakaria. Circulating cytokines, chemokines, and small molecules follow distinct expression patterns in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B86.
Abstract IA09: RiboSeq and ye shall find: Noncanonical protein translation in cancer Iimunosurveillance
Authors: Yewdell Jonathan W. 
Published: February 2019

Abstract
By displaying oligopeptides on the cell surface, class I major histocompatibility complex (MHC-I) molecules enable CD8+ T cell immunosurveillance of tumor cells. MHC-I peptide ligands derive proteins synthesized by cancer cells. A number of lines of evidence indicate that many MHC-I peptides derive from a pool of rapidly degraded defective ribosomal products (DRiPs). DRiPs include misfolded gene products resulting from errors in transcription, translation, folding, targeting, and assembly. They also encompass the translation products of “immunoribosomes,” specialized ribosomes proposed to generate antigenic peptides for the express propose of immunosurveillance. There are now several examples in which noncanonical translation efficiently generates peptides for immunosurveillance. I will discuss how the method of ribosome profiling can be used to identify novel tumor target peptides for immunotherapy arising from noncanonical translation. To determine whether ribosome heterogeneity itself can also selectively increase antigenic peptide generation, we screened a lentiviral shRNA library targeting each of the 80 human ribosomal protein genes. We identified candidate genes by alterations in steady state class I molecule expression (a measure of overall peptide supply) or in the ratio of source proteins to source protein-derived peptides. Two ribosomal proteins that either increase or decrease the efficiency of peptide generation are near neighbors on the ribosome surface, suggesting possible mechanisms for influencing peptide generation.
Citation Format: Jonathan W. Yewdell. RiboSeq and ye shall find: Noncanonical protein translation in cancer Iimunosurveillance [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA09.