bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A77: Cripto-1 vaccination elicits protective immune response to metastatic breast cancer and breast cancer stem cells
Authors: Witt Kristina , Ligtenberg Maarten Alexander , Conti Laura , Lanzardo Stefania , Ruiu Roberto , Tufvesson-Stiller Helena , Ostling Jeanette , Rolny Charlotte , Lladser Alvaro , Lundqvist Andreas , Cavallo Federica , Kiessling Rolf
Published: February 2019

Metastatic breast cancer is a fatal disease responding poorly to classical treatments. Cancer vaccines targeting antigens expressed by metastatic breast cancer and cancer stem cells (CSC) have the potential to become potent anti-cancer therapies. Cripto-1 is an onco-fetal protein frequently overexpressed in invasive breast cancer and cancer-initiating cells. It is involved in cellular processes such as cell migration, epithelial-mesenchymal transition, and invasion, hallmarks of aggressive cancers. In this study we explored the potential of a Cripto-1 encoding DNA vaccination to target metastatic breast cancer and breast cancer stem cells in preclinical models.

Mice were vaccinated with a DNA vaccine encoding for mouse Cripto-1 (mCR) prior tumor challenge. In the 4T1 metastatic breast cancer model vaccination against mCR resulted in reduced primary tumor growth and significantly reduced metastatic burden in the lung. We further identified Cripto-1 specific antibodies in this model generated by the vaccination. TUBO is a Cripto-1 negative breast cancer cell line and vaccination against mCR in the transplantable BALB/c TUBO model did not result in protection. We show that spheroid culture of TUBO results in up-regulation of Cripto-1 on the cell surface. In addition, TUBO spheres display cancer stem cell phenotype. Consequently, tumor progression was inhibited in anti-mCR vaccinated mice challenged with TUBO spheres but not in control vaccinated mice.

Our data indicates that DNA vaccination against Cripto-1 results in a protective immune response against mCR expressing tumors. Targeting Cripto-1 by vaccination is a promising potential immunotherapy for treatment of metastatic breast cancer.

Citation Format: Kristina Witt, Maarten Alexander Ligtenberg, Laura Conti, Stefania Lanzardo, Roberto Ruiu, Helena Tufvesson-Stiller, Jeanette Ostling, Charlotte Rolny, Alvaro Lladser, Andreas Lundqvist, Federica Cavallo, Rolf Kiessling. Cripto-1 vaccination elicits protective immune response to metastatic breast cancer and breast cancer stem cells [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 A77.
Abstract A78: Analysis of ROR1 protein expression in mice with reconstituted human immune system components
Authors: Leung Carol SK
Published: February 2019

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal antigen expressed on multiple solid tumors and leukemias, but not on normal human tissues except at very low levels in adipose tissue. ROR1 is highly upregulated in chronic lymphocytic leukemia (CLL) B cells. NOD-scid IL2rγnull (NSG) mice engrafted with human fetal liver CD34+ hematopoietic progenitor cells (huNSG) achieved multi-lineage human immune cell reconstitution including B cells, T cells, NK cells and Dendritic cells. Like the CLL patients, most of huNSG mice have abnormal high frequency of B cells in the periphery, and a percentage of CD19+ B cells express CD5. In light of this, we aim to determine whether ROR1 is expressed in B cells of huNSG mice, we analyzed the protein level of ROR1 in B cells of huNSG mice by flow cytometry. ROR1 protein was highly expressed in a proportion of B cells in the blood, spleen and bone marrow. As huNSG mice have autologous T and NK cells, plus the B cells with ROR1 expression, this could act as a B cell malignant disease model for studying immunotherapeutic targeting ROR1, including bispecific T cell engagers and chimeric antigen receptor T cells.

Citation Format: Carol SK Leung. Analysis of ROR1 protein expression in mice with reconstituted human immune system components [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 A78.
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

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 (< 0.2 g/mouse, i.p.) synergistically suppressed tumor growth comparing to untreated and single-treated controls (p< 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

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

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

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

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

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

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 < 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

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 <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

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.
Abstract IA11: Developing and improving personalized neoantigen-targeting cancer vaccines
Authors: Wu Catherine J.
Published: February 2019

At the heart of any cancer and host immune cell response is the tumor antigen and host antigen-specific T-cell interaction. The cytotoxic T cell-cognate antigen interaction forms the mechanistic basis for immune-mediated recognition and the killing of malignant cells. While the search for immunogenic tumor antigens has been the subject of decades-long studies, multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. Using next-generation sequencing approaches, we can now systematically identify mutations leading to amino acid changes that can be potentially recognized immunologically through the implementation of neoantigen discovery pipelines. In recent studies, we have tested the feasibility and immunogenicity of a vaccine that targets up to 20 personal neoantigens predicted to be presented by autologous patient tumor. This approach can expand the repertoire of neoantigen-specific T cells, providing a strong rationale for the further development of this approach, alone and in combination with checkpoint therapies.

Citation Format: Catherine J. Wu. Developing and improving personalized neoantigen-targeting cancer vaccines [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 IA11.
Abstract IA29: Novel insights into the dose-dependency of radiation immunogenicity
Authors: Demaria Sandra
Published: February 2019

Recruitment to the tumor of a Batf3-dependent subset of dendritic cells (DCs) specialized in cross-presentation of tumor-derived antigens to CD8+ cytotoxic T cells is driven by type I interferon (IFN-I) and is essential for activation of antitumor CD8+ T cells. We have recently found that in tumors refractory to treatment with immune checkpoint blockers (ICBs), radiotherapy induces cancer cell-intrinsic activation of IFN-I pathway and release of interferon-beta, mimicking a viral infection, and resulting in recruitment of Batf3-dependent DCs (Vanpouille-Box et al., Nat Commun 2017). This process is mediated by the accumulation of dsDNA in the cancer cell cytoplasm, which is sensed by cGAS and leads to downstream activation of STING. Importantly, the dose and fractionation of radiation are critical for optimal induction of IFN-I production by irradiated cancer cells. For most carcinoma cells there is a single radiation dose threshold of 12-15 Gy above which the DNA exonuclease TREX1 is upregulated. The latter degrades cytoplasmic dsDNA precluding IFN-I activation. Fractionation, i.e., repeated (three times) daily delivery of radiation therapy at doses below this threshold, amplifies the IFN-I pathway activation in the carcinoma cells, an effect that requires upregulation of IFNRA. Furthermore, the synergy of RT with ICBs (anti-CTLA-4 or anti-PD-1) and the induction of abscopal effects (i.e., immune-mediated rejection of nonirradiated synchronous tumors) are completely dependent on the ability of radiotherapy to induce cancer cell-intrinsic IFN-I.

These findings have critical implications for the use of radiotherapy to increase the response to ICBs in the clinic, a strategy currently being tested in over one hundred ongoing and planned trials.

Supported by NIH 1R01CA201246, Breast Cancer Research Foundation BCRF-016-054, and The Chemotherapy Foundation.

Citation Format: Sandra Demaria. Novel insights into the dose-dependency of radiation immunogenicity [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 IA29.
Abstract IA30: Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures
Authors: Allison James P.
Published: February 2019

The existence of multiple nonredundant inhibitory pathways that limit T-cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen-presenting cells. Antibodies to CTLA-4 have proved effective against multiple tumor types in both preclinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long-term (>4 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late-stage melanoma. In 2011 it was approved by the FDA for treatment of late-stage melanoma and is now a standard of care for that disease.

PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T-cell antigen receptor-mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late-stage melanoma patients. Altogether, the FDA has approved 17 checkpoint antibodies/indications for melanoma and lung cancer.

Emerging data suggest that T-cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, it is becoming clear that certain types of tumors with lower burdens of mutations (e.g., prostate, breast, and kidney cancer) present special challenges for immune therapy. Strategies for effective treatment of such tumors will be discussed.

We have also used high-parameter flow cytometry to identify the cellular mechanisms of CTLA-4 and PD-1 blockade. These are mostly nonoverlapping, which may be a partial explanation for the enhanced effect of the combination.

Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures [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 IA30.
Abstract PR08: Metabolic adaptations establish immunotherapy resistance in melanoma
Authors: Jaiswal Ashvin R. , Pudakalakatti Shivanand , Dutta Prasanta , Liu Arthur , Bartkowiak Todd , Ager Casey , Ivan Cristina , Davis Richard Eric , Davies Michael A. , Wargo Jennifer , Allison James P. , Bhattacharya Pratip K. , Hong David , Curran Michael A.
Published: February 2019

Background: Despite the success of T-cell checkpoint blockade antibodies in treating an array of cancers, the majority of patients still fail to respond to these therapies, or respond transiently and then relapse. The molecular mechanisms that drive lack of response to checkpoint blockade, whether pre-existing or evolved on therapy, remain unclear.

Materials and Methods: To address this critical gap in clinical knowledge, we established a mouse model of melanoma designed to elucidate the molecular mechanisms underlying immunotherapy resistance. Through multiple in vivo passages, we selected a B16 melanoma tumor line that evolved complete resistance to combination blockade of CTLA-4, PD-1, and PD-L1, which cures ~80% of mice of the parental tumor. Using gene expression analysis, proteomics, and immunogenomics, we determined the adaptations engaged by this melanoma to become completely immunotherapy resistant. NMR spectroscopy, Seahorse XF analysis, flow cytometry, confocal microscopy, and Western blot analysis provided further insight into the mechanisms driving checkpoint blockade resistance.

Results: Acquisition of immunotherapy resistance by these melanomas was driven by coordinate upregulation of the glycolytic and aldose reductase pathways to create a metabolically hostile microenvironment in which T-cell function is profoundly suppressed. When reintroduced into the parental tumor, the genes most closely associated with these metabolic adaptations confer enhanced immunotherapy resistance. We have validated upregulation of these pathways in a unique cohort of melanoma patients who failed dual checkpoint blockade. Additionally, we employed MRI imaging to visualize metabolic changes acquired by resistant tumors in live mice. Clinical application of this technique could provide a much-needed noninvasive tool to predict immunotherapeutic sensitivity of patients.

Conclusion: Upregulation of glycolytic metabolism and the aldose reductase pathway by melanoma tumor cells cripples T cells in the microenvironment and confers resistance to checkpoint blockade.

This abstract is also being presented as Poster A71.

Citation Format: Ashvin R. Jaiswal, Shivanand Pudakalakatti, Prasanta Dutta, Arthur Liu, Todd Bartkowiak, Casey Ager, Cristina Ivan, Richard Eric Davis, Michael A. Davies, Jennifer Wargo, James P. Allison, Pratip K. Bhattacharya, David Hong, Michael A. Curran. Metabolic adaptations establish immunotherapy resistance in melanoma [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 PR08.
Ameliorative Effect of Cardamom Aqueous Extract on Doxorubicin-Induced Cardiotoxicity in Rats
Authors: Abu Gazia Maha , El-Magd Mohammed Abu
Published: February 2019

This study was conducted to evaluate the potential cardioprotective effect of cardamom (CAR) against myocardial injuries induced by doxorubicin (DOX) in rats through investigation of histological alterations and the associated oxidative stress, apoptosis, inflammation, and angiogenesis. This study included 30 adult male albino rats that were randomized to 3 groups (n = 10/group): group I (control), group II (DOX) rats injected with DOX (2.5 mg/kg body weight [BW] i.p.) every other day for 2 weeks, and group III (CAR+DOX) received CAR extract (200 mg/kg BW) orally for 3 weeks, and 1 week later (starting from the 2nd week) they were injected with DOX (2.5 mg/kg BW i.p.) every other day for 2 weeks. Rats treated with DOX alone exhibited notable myocardial damage (discontinuity and disorganization of cardiac muscle fibers, mononuclear cell infiltration, and apparent increases in collagen fiber deposition) accompanied by loss of function (revealed by elevated serum levels of lactate dehydrogenase, creatine kinase, and cardiac troponin), induction of oxidative stress (indicated by higher levels of nitric oxide and malon­dialdehyde, and lower levels of superoxide dismutase, catalase, and glutathione peroxidase), apoptosis (evidenced by high caspase 3 activity and immunostaining), and inflammation (marked by high cardiac NFκB level). However, administration of CAR not only ameliorated all deleterious effects of DOX but also induced angiogenesis, as indicated by a significant increase in VEGF immunoreactivity. These data indicate that CAR could relieve DOX-induced cardiotoxicity, at least in part, via reductions in oxidative stress, apoptosis, and inflammation and increased tissue regeneration via induction of angiogenesis. Therefore, CAR could be a promising cytoprotective agent against DOX cardiotoxicity.
Fármacos inovadores em saúde mental
Authors: Macedo Júlia Borges de , Pereira Airton Vicente , Perek Karyn Vanessa , Karas Laís Priscila
Published: February 2019

Apesar do aumento global das doenças mentais, os investimentos destinados à pesquisa de novos fármacos apresentaram uma redução expressiva na última década, fato que pode impactar negativamente na descoberta de fármacos inovadores. Os fármacos aprovados pelo FDA entre 1997 e 2017 nas áreas de neurologia e psiquiatria foram avaliados e classificados em seis diferentes categorias para identificar os fármacos inovadores para o tratamento de doenças mentais. No período avaliado, foram 192 aprovações, sendo 139 em neurologia e 53 em psiquiatria. Os resultados mostram uma tendência de diminuição do número de aprovações e inovações, com apenas 28 fármacos inovadores (14,6%), sendo os demais classificados como análogos estruturais, pró-fármacos, novas formulações, novo emprego terapêutico ou associações de fármacos. Os fármacos inovadores para doenças mentais foram aprovados somente para as doenças de Parkinson (4), Alzheimer (1) e transtorno de déficit de atenção e hiperatividade (1), enquanto nenhuma inovação ocorreu para doenças importantes como depressão, esquizofrenia e transtorno bipolar.
Being Soviet, Muslim, Modernist, and Fundamentalist in 1950s Central Asia
Authors: Sartori Paolo , Babajanov Bakhtiyar
Published: February 2019

How far, if at all, did the intellectual legacy of early 20th-century Muslim reformism inform the transformative process which Islam underwent in Soviet Central Asia, especially after WWII? Little has been done so far to analyze the output of Muslim scholars (ʿulamāʾ) operating under Soviet rule from the perspective of earlier Islamic intellectual traditions. The present essay addresses this problem and sheds light on manifestations of continuity among Islamic intellectual practices—mostly puritanical—from the period immediately before the October Revolution to the 1950s. Such a continuity, we argue, profoundly informed the activity of the Spiritual Administration of the Muslims of Central Asia and Kazakhstan (SADUM) established in Tashkent in 1943 and, more specifically, the latter’s attack against manifestations of religiosity deemed “popular,” which were connected to the cult of saints. Thus, this essay posits that the juristic output of Soviet ʻulamā’ in Central Asia originates from and further develops an Islamic reformist thinking, which manifested itself in the region in the late 19th- and early 20th-century. By establishing such an intellectual genealogy, we seek in this article to revise a historiographical narrative which has hitherto tended to decouple scripturalist sensibilities from Islamic reformism and modernism.
The Text and Metre of Sapph. fr. 114 V.
Authors: Meister Felix J.
Published: February 2019

This article aims to address the problems posed by Sappho’s difficult fr. 114 V. It first revises the assumption that both lines need to display the same metrical profile and concludes that this assumption is unreliable. Then it offers a reconstruction of the fragment that is not restricted by the alleged need for metrical homogeneity.
Royal Wet Nurses in Seventh- and Early Eighth-Century China: Historiographical Evaluation and Narrative Construction
Authors: Doran Rebecca
Published: February 2019

The women who served as wet nurses to powerful and in some cases notorious members of the Tang royal family appear in written materials in various capacities in relation to prominent historical actors. An analysis of historical narratives involving these women indicates that their portrayals were strongly influenced by the historian’s mode of moral assessment, in particular, the historical judgment meted out upon their controversial charges. The manipulation in historical narrative of royal wet nurses thus elucidates a fascinating example of the operation of “praise and blame” in traditional historiography. Wet nurses are used as narrative pawns to emphasize the historical judgment of their famous former charges and become a vehicle or mouthpiece for historical evaluation.
Aristotle on Virtue of Character and the Authority of Reason
Authors: Müller Jozef
Published: February 2019

I argue that, for Aristotle, virtue of character is a state of the non-rational part of the soul that makes one prone to making and acting on decisions in virtue of that part’s standing in the right relation to (correct) reason, namely, a relation that qualifies the agent as a true self-lover. In effect, this central feature of virtue of character is nothing else than love of practical wisdom. As I argue, it not only explains how reason can hold direct authority over non-rational desires but also why Aristotle defines virtue of character as hexis prohairetikē.
Some Cases of Root Exegesis of Hebrew Forms in Peshitta Ezekiel
Authors: Lund Jerome A.
Published: February 2019

The new translation of Peshitta Ezekiel by Gillian Greenberg and Donald M. Walter in the Bible of Antioch series raises issues with regard to the interpretation of the Syriac text and its relationship to the Hebrew. The Syriac translator used root exegesis of Hebrew forms as a translation tool. This study will examine a number of cases of root exegesis in Peshitta Ezekiel with the aim of better understanding the Peshitta translation. This research was undertaken as part of the Bible of Edessa project.
The Helpful God: A Reevaluation of the Etymology and Character of (ˀēl) šadday
Authors: Wilson-Wright Aren M.
Published: February 2019

Both the role of the deity (El) Shadday in the religions of ancient Israel and the etymology of the name šadday remain poorly understood. In this article, I will propose a new etymology for the name šadday and then leverage this etymology into a better understanding of (El) Shadday’s character. I argue that šadday is a nomen agentis from the root sdy ‘to help’ and originated as an epithet of the deity El, which highlighted his benevolent qualities. A comparison of El in the Ugaritic epics and El Shadday in the Priestly Source (P) suggests that El Shadday was thought to help his worshippers by providing them with children. El Shadday thus represents one way in which the deity El survived in the religions of ancient Israel.
Testing the causal understanding of water displacement by kea (Nestor notabilis)
Authors: Schwing R. , Weiss F. , Tichy A. , Gajdon G.
Published: February 2019

Rooks, Eurasian jays and NC crows have already solved the Aesop’s fable paradigm, using stones to raise a water level to get a previously out of reach reward. Here we test kea parrots on their understanding of water displacement. In Experiment 1, they preferentially chose the water-filled tube over two solid substrates (sand, rocks) within 5 trials. In Experiment 2, they generalised to novel coloured substrates in the first trial. In Experiment 3, confronted with two water-filled tubes, one of which was made unsolvable by preventing the water from rising, none of the kea managed to solve the task. This suggests that their performance in Experiments 1 and 2 was reward association with the liquid-filled tube, without attendance to changes in water level. These results therefore provide no evidence of causal understanding of water displacement and highlight that such an understanding is not required for solving Aesop’s Fable.
Fusion Politics from the Poor People’s Campaign to the Rainbow Coalition to the New Poor People’s Campaign
Authors: Sinclair-Chapman Valeria , Targ Harry
Published: February 2019

This article examines a model of fusion politics that connects activism to end poverty, and addresses a constellation of social injustices across more than a half century in the United States. We consider an articulation of fusion politics that highlights the actions of disparate groups and individuals, including youth, racial and ethnic minorities, women, LGBT activists, teachers, and union members who have joined in a cooperative effort to address independent but linked concerns such as quality public schools, livable wages, affordable healthcare, environmental justice, immigrant rights, women’s reproductive rights, fair elections, and criminal justice. Our analysis points out the historical links between the 1968 Poor People’s Campaign, the Rainbow Coalition of the 1980s, and the new Poor People’s Campaign launched in 2018. It draws heavily on the words and writings of Reverend Martin Luther King, Jr. and the Reverend William Barber, II in understanding the organizing, objectives, and transformative potential of these movements.