bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B089: Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells
Authors: Velmurugan Ramraj , Challa Dilip , Ram Sripad , Ober Raimund , Ward E. Sally 
Published: May 2016

Abstract
The interplay between innate immune cells and antibodies to control cancerous growth is of central importance for mediating direct anti-tumor effects and the induction of long-lived anti-tumor immunity. Phagocytosis of antibody-opsonized cells by macrophages through Fc gamma receptor interactions is well characterized and leads to cell death through target cell engulfment into phagosomes. By contrast, the contribution of the related process called trogocytosis, involving the ingestion of limited amounts of the target cell by phagocytic cells, to cell attrition is less certain. In the current study we have developed a high throughput, quantitative assay to distinguish whole cell phagocytosis and trogocytosis for different macrophage:breast cancer cell combinations. These analyses, combined with long term microscopic imaging, demonstrate that trogocytosis leads to death of HER2-overexpressing breast tumor cells. The implementation of multifocal plane microscopy to investigate trogocytic events at high spatiotemporal resolution reveals that these processes involve tubular extensions of opsonized tumor cells that are subsequently pinched off by the recipient macrophage. Of relevance to the design of second generation antibodies with improved efficacy, antibody engineering to enhance Fc gamma receptor interactions results in increased trogocytic activity. Collectively, these studies have significance to the rapidly expanding use of antibodies to treat cancer.
This research was supported in part by grants from the Cancer Prevention and Research Institute of Texas (CPRIT, RP 110069) and the National Institutes of Health (R01 GM85575).
Citation Format: Ramraj Velmurugan, Dilip Challa, Sripad Ram, Raimund Ober, E. Sally Ward. Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B089.
Abstract B112: Identifying determinants of melanoma response to immune checkpoint inhibitors via preclinical modeling
Authors: Day Chi-Ping , Meskini Rajaa El , Graff-Cherry Cari , Michalowski Aleksandra , Ohler Zoe Weaver , Dyke Terry Van , Merlino Glenn 
Published: May 2016

Abstract
Immune checkpoint inhibitors (ICPi; e.g. anti-CTLA-4, anti-PD-1, anti-PD-L1) have shown great promise for melanoma treatment; however, sustained responses are achieved only in a fraction of patients, while the majority does not respond at all. Though load and patterns of mutations have been shown to be associated with IMT responses, the determinants have never been well characterized. In this study we aimed to identify predictive markers of melanoma response to ICPi by preclinical modeling. Three genetically engineered mice (GEM) were built to model melanomagenesis driven by different carcinogenic processes: (1) UV in albino BRAF(V600E); PTEN-knockout C57BL/6 mice, (2) carcinogen DMBA in pigmented Hgf-tg; CDK4(R24C) C57BL/6 mice, and (3) UV in pigmented Hgf-tg C57BL/6 mice. Melanoma cells derived from these models were subjected for exome sequencing and immunogenicity test by vaccination and challenge. Their responses to anti-CTLA-4 antibody were then tested in preclinical settings. Model (1), (2) and (3) are non-, medium-, and high-immunogenic, respectively. Consistent with published data, responses to anti-CTLA-4 are well correlated with the immunogenicity of individual melanoma models. Moreover, co-administration of BRAF or MEK inhibitors with immunotherapy did not enhance therapeutic efficacy. Based on exome sequencing, all the models exhibit coding mutations in genes of neuronal development, MAPK pathways, and G protein-coupled pathways, but UV-type mutations (C to T and G to A) were enriched only in model (1). Interestingly, deleterious mutations in DNA damage response (DDR) genes existed only in immunogenic models (2) and (3). These results suggested that carcinogenic mechanisms determine tumor immunogenicity and therefore response to IMT. Consistent with recent data from clinical studies, mutations in DDR genes may be predictive of IMT response. Currently we are evaluating the functions of specific DDR genes in melanoma, and the possibility they may serve as therapeutic targets in combination therapies with ICPi.
Citation Format: Chi-Ping Day, Rajaa El Meskini, Cari Graff-Cherry, Aleksandra Michalowski, Zoe Weaver Ohler, Terry Van Dyke, Glenn Merlino. Identifying determinants of melanoma response to immune checkpoint inhibitors via preclinical modeling. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B112.
Abstract B118: Preclinical model of patient-derived tumor transplant in humanized mice for cancer immunotherapy
Authors: Wulf-Goldenberg Annika , Stecklum Maria , Fichtner Iduna , Hoffmann Jens 
Published: May 2016

Abstract
The identification and validation of new targets for antitumor immune therapy is still a challenge for the preclinical research as the classical syngeneic tumor models are of limited translational value and patient-derived human tumor xenograft models (PDX) are growing on immunodeficient animals.
To overcome these constraints our aim is the development of PDX models on mice with a functional human immune system to improve predictability of drug efficacy and safety.
We reconstituted a human immune system by engrafting human hematopoietic stem cells isolated from cord blood in immunodeficient mice. A stable expression of lymphoid cell lineages in peripheral blood and secondary lymphoid tissues could be detected by flow cytometry and immunohistochemistry analysis.
At the time when the human immune system is developed, established patient-derived tumors were transplanted on these humanized mice. Human tumors developed on humanized mice without evidence of rejection. Tumors from different tumor entities grow on humanized mice with a similar level of engraftment compared to not-humanized mice.
We also tested the effect of ipilimumab (anti-CTLA-4 [cytotoxic T-lymphocyte antigen-4] mAB) and the humanized monoclonal antibody herceptin in these tumor-bearing humanized mice. We found ipilimumab could lead to a slight tumor growth delay and an increased percentage of T-cells in the blood and in the tumor.
Initially results revealed that our humanized mouse models could enable a more appropriate preclinical assessment of immune-based therapeutic antitumor strategies especially when combining the humanized mouse with patient-derived xenografts.
Citation Format: Annika Wulf-Goldenberg, Maria Stecklum, Iduna Fichtner, Jens Hoffmann. Preclinical model of patient-derived tumor transplant in humanized mice for cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B118.
Abstract B127: Tumor eradication in a murine model of glioma with vaccination and anti-CTLA-4 but not anti-PD-1
Authors: Field Cameron S. , Hunn Martin K. , Ferguson Peter M. , Yagita Hideo , Hermans Ian F. , Ancelet Lindsay R. 
Published: May 2016

Abstract
Vaccine-mediated cancer treatment is generally insufficient to bestow long-term survival unless suppressive mechanisms are overcome. Given the success of antibody-mediated immune checkpoint blockade in relieving suppression of anti-tumor T cell responses that develop naturally in tumor-burdened hosts, we investigated whether checkpoint blockade can be used to improve the efficacy of vaccine-induced T cell responses. Combining an adjuvanted whole-cell vaccine with antibodies to cytotoxic T lymphocyte antigen-4 (α-CTLA-4) resulted in regression of established intracranial tumors, whereas neither treatment was effective as a monotherapy. In contrast, combining the vaccine with antibodies to programmed death-1 (α-PD-1) failed to provide any survival advantage despite α-PD-1 being effective against the same tumor implanted subcutaneously, which was attributed to poor access of α-PD-1 to T cell effectors in the brain. The effective combination of vaccine and α-CTLA-4 was associated with enhanced proliferation and accumulation of T cells in the lymphoid tissues without any obvious changes in the stimulatory function of antigen-presenting cells or the number of regulatory T cells, suggesting recently primed T cells were the targets of checkpoint inhibition. While tumors regressing under this combined treatment were highly infiltrated with a variety of leukocytes, tumor eradication was strictly dependent on CD4+ T cells. These results demonstrate that vaccination can be combined effectively with checkpoint blockade to induce effective T cell-mediated responses against glioma. However, new strategies are required to improve access of inhibitors to the brain if immune checkpoints on intratumoral effector cells are to be targeted.
Citation Format: Cameron S. Field, Martin K. Hunn, Peter M. Ferguson, Hideo Yagita, Ian F. Hermans, Lindsay R. Ancelet. Tumor eradication in a murine model of glioma with vaccination and anti-CTLA-4 but not anti-PD-1. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B127.
Abstract B136: Development of PD-L1/L2 over-expressing mouse liver cancer models to test the efficacy of anti-PD1 therapy for hepatocellular carcinoma
Authors: Ou Da-Liang , Chen Shu-Ching , Su Yu-Chia , Cheng Ann-Lii , Hsu Chiun 
Published: May 2016

Abstract
Anti-PD1 therapy has shown promising anti-tumor activities in multiple cancer types, including hepatocellular carcinoma (HCC), and PD-L1 expression in tumor cells was considered a potential predictive marker for treatment efficacy. The present study explored whether PD-L1/L2 expression may affect treatment efficacy of anti-PD1 therapy for HCC. PD-L1 (MR203953; Origene Technologies, Rockville, MD) or PD-L2 (MR222499; Origene Technologies) was transfected into the BNL-MEA murine liver cancer cell lines and stable clones were selected. Effects of PDL1/L2 over-expression were confirmed by Western blotting and immunofluorescence assay. Effects of PDL1/L2 over-expression on in vitro growth characteristics were compared by MTT, colony formation, and 3-D culture assays. Orthotopic liver cancer models were established by sub-capsular injection of parental or transfected cancer cells into the left lobe of mouse liver. The anti-tumor efficacy of anti-mouse PD1 therapy (clone 4H2, Ono Pharmaceutical Co), 0.2 mg by intraperitoneal injection on day 5, 8, 11, 14, and 17 after tumor implantation, was measured by change in tumor volume using the orthotopic liver cancer models. Distribution of T-cell sub-populations in tumor-infiltrating lymphocytes (TILs) after treatment were measured by flow cytometry.
The growth characteristics of parental and PD-L1/L2-expressing BNL-MEA cells did not differ significantly, as measured by MTT, colony formation, and 3-D culture assays. Survival of animals bearing the orthotopic liver tumor with or without PD-L1/L2 over-expression was also similar. Anti-PD1 therapy appeared more efficacious in PD-L1-over-expressing liver cancer models than the parental or PD-L2-over-expressing models. Distinctive TILs distribution patterns between parental and PD-L1/L2 over-expressing liver cancer models were found after anti-PD1 therapy.
Conclusions: The PD-L1/L2 expressing liver cancer models may help evaluate the efficacy and mechanisms of action of anti-PD1 therapy for HCC.
Citation Format: Da-Liang Ou, Shu-Ching Chen, Yu-Chia Su, Ann-Lii Cheng, Chiun Hsu. Development of PD-L1/L2 over-expressing mouse liver cancer models to test the efficacy of anti-PD1 therapy for hepatocellular carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B136.
Abstract B172: Oncogene-mediated immune microenvironments in lung cancer provide a rationale for combination therapies
Authors: Havel Lauren S. , Gao Dingcheng , Altorki Nasser , Mittal Vivek 
Published: May 2016

Abstract
Non-small cell lung cancer (NSCLC) constitutes ~80% of all lung cancer cases and has a 5-year survival rate of only 15-20%. Over the past decade, targeted therapies have shown some efficacy in NSCLC patients who present drug sensitive mutations. However, acquired drug resistance has been a major obstacle to achieving durable responses. Novel and more effective combinatorial treatments are urgently needed in the clinic to improve the dismal prognosis of NSCLC patients. Recently, immune checkpoint inhibitors have led to durable response rates in NSCLC patients of up to 25%, but a large portion of patients continue to show minimal or no response. Notably, the mechanisms responsible for regulating the tumor's response to immune checkpoint inhibitors have not been elucidated. There is increasing evidence that oncogenes modulate expression of immune regulatory genes, leading to the notion that therapies that target specific oncogene pathways may influence diverse aspects of the immune response. To this end, we have focused on mouse models of NSCLC carrying mutations in the KRAS or EGFR oncogenes or the EML4-ALK translocation. These mutations were chosen because 1) together they account for &gt;40% of the NSCLC patients and 2) FDA approved targeted therapies are available for EML4-ALK and EGFR mutants. We have performed comprehensive immunophenotyping in each of these models and observed mutation-specific distribution and abundance of specific immune subsets, suggesting diverse mechanisms and varying degrees of immune invasion/exclusion. These findings have predictive value in determining which tumor has the most likelihood of responding to specific immune checkpoint inhibitors (anti-PD-1, anti-PD-L1 or anti-CTLA4). We will discuss the implication of this approach in improving response rates to other standard of care treatments such as targeted therapies, radiation and/or chemotherapy in combination with the checkpoint inhibitors. Overall, this work has the potential to provide a mechanism-based rationale for combining standard of care treatments and immunotherapies for the treatment of NSCLC.
Citation Format: Lauren S. Havel, Dingcheng Gao, Nasser Altorki, Vivek Mittal. Oncogene-mediated immune microenvironments in lung cancer provide a rationale for combination therapies. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B172.
Abstract IA20: Cancer subtypes and their immune microenvironments
Authors: Becht Etienne , Giraldo Nicolas A. , Reynies Aurelien De , Laurent-Puig Pierre , Beuselinck Benoit , Zucman-Rossi Jessica , Dieu-Nosjean Marie Caroline , Sautes-Fridman Catherine , Fridman Wolf H. 
Published: May 2016

Abstract
In the vast majority of cancer types, as demonstrated and exemplified in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC), a high density of CD8+ T cells associated with high densities of tertiary lymphoid structures (TLS) in the tumor microenvironment correlates with a good prognosis for the patient. However, an opposite association has been reported in primary clear cell renal cell carcinoma (RCC) and several other cancers. Our team studied the immune infiltrates of pulmonary metastases from CRC and RCC. As in the primary tumors, a high density of CD8+ T cells correlated with good prognosis for CRC metastases, while it correlated with a bad prognosis for RCC metastases. These results suggested that the identity of the tumor cells, rather than the organ where they grow, is critical for shaping the immune contexture of a given tumor.
Transcriptomic analyses of large cohorts of human CRC and RCC allow to define molecular subgroups associated with distinct risks of tumor progression. We therefore characterized the immune microenvironments of the molecular subgroups of CRC and RCC. In CRC, the MSI-enriched subgroup identified patients with high cytotoxic T cells infiltration and favorable prognosis. In CRC and RCC, we confirmed that patients with low tumoral T and B cell infiltrations presented with high risk of death; In addition, in both cancer types, we identified subgroups of poor-prognosis patients with high tumoral lymphocyte infiltration, in the context of high expression of genes related to inflammation, immunosuppression, and angiogenesis.
Integration of molecular and immune tumor phenotypes refines prognostic cancer groups. Moreover, these classifications allow to select immunotherapies appropriate to specific, potentially responding, groups of patients.
Citation Format: Etienne Becht, Nicolas A. Giraldo, Aurelien De Reynies, Pierre Laurent-Puig, Benoit Beuselinck, Jessica Zucman-Rossi, Marie Caroline Dieu-Nosjean, Catherine Sautes-Fridman, Wolf H. Fridman. Cancer subtypes and their immune microenvironments. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA20.
Abstract IA23: T cell memory and exhaustion
Authors: Ahmed Rafi 
Published: May 2016

Abstract
Chronic antigen stimulation during persistent infections or cancer leads to functional exhaustion of CD8 T cells. The inhibitory receptor PD-1 plays a major role in this T cell dysfunction and blockade of this inhibitory pathway restores function in exhausted T cells. T cell exhaustion and the role of PD-1 in chronic infection were first documented in the mouse model of chronic LCMV infection and these findings were then extended to chronic viral infections in non-human primates and humans. In this talk I will discuss combinatorial strategies that enhance PD-1 directed immunotherapy and describe how PD-1 blockade acts not only at the level of increasing T cell numbers but plays a key role in target cell elimination. An interesting aspect of PD-1 biology is that PD-1 is also expressed during the early phase of T cell activation. In this talk I will also discuss how this early PD-1 expression is regulated and its potential role in CD8 T cell differentiation.
Citation Format: Rafi Ahmed. T cell memory and exhaustion. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA23.
Abstract IA32: Commensal microorganisms and polymorphic mucosal surfaces determine the evolution of distal metastatic tumors
Authors: Rutkowski Melanie R. , Conejo-Garcia Jose R. 
Published: May 2016

Abstract
Humans are symbiotic organisms in which bacteria outnumber eukaryotic cells in a ratio of 10 to 1. Interactions between commensal microorganisms and immune cells at mucosal surfaces forge the orchestration of a robust immune system that is able to defend us from infections. Critical for these interactions are pattern recognition receptors, including TLRs, which exhibit functional polymorphisms in at least 30% of individuals in the general population.
We show that TLR5 recognition of commensal bacteria drives malignant progression at distant, extra-mucosal locations by promoting systemic up-regulation of IL-6, which is further increased through an autocrine loop in reactive tumor cells and drives MDSC mobilization. MDSCs expanded in response to systemic IL-6 elevation produce adenosine to transform T cells into immunosuppressive players that secrete higher levels of galectin-1 on a per cell basis than any other cell type in the tumor microenvironment.
In contrast, in TLR5-unresponsive individuals, there is systemic up-regulation of IL-17 during tumor development. However, this is only relevant for tumor growth when tumors generate relatively low levels of circulating IL-6, resulting in accelerated malignant progression in the absence of TLR5 signaling.
Importantly, depletion of commensal bacteria abrogates any variations in tumor progression and has opposite effects in tumors that grow faster in TLR5-competent individuals (delaying malignant progression) vs. tumors that progress faster in the absence of TLR5 signaling (where malignant progression is accelerated).
Shockingly, depletion of commensal bacteria has opposite effects in the progression of primary vs. metastatic breast tumors, thus opening new avenues to understand breast cancer recurrence and tumor dormancy.
Together, our data indicate that both tumor-promoting inflammation and anti-tumor immunity are influenced by TLR5 signaling, which depends on a common genetic polymorphism in cancer patients.
Citation Format: Melanie R. Rutkowski, Jose R. Conejo-Garcia. Commensal microorganisms and polymorphic mucosal surfaces determine the evolution of distal metastatic tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA32.
Abstract IA33: Biofilms, genetics, and colon cancer
Authors: Sears Cynthia L. 
Published: May 2016

Abstract
The colonic microbiota perhaps aided by specific bacterial species is hypothesized to contribute to colon cancer pathogenesis. Potential mechanisms include induction of mucosal pro-carcinogenic immune responses and the biologic action of specific microbial, particularly bacterial, virulence factors. Among specific bacterial species, Escherichia coli possessing the pks island with the DNA-damaging colibactin toxin, Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis (ETBF) that secretes the DNA-damaging B. fragilis toxin are carcinogenic species of particular interest. To address the hypothesis that microbial species or communities contribute to CRC pathogenesis, we are prospectively studying the microbial associations of human CRC together with parameters of mucosal immunity. The epidemiology of specific putative carcinogenic bacterial species and the relationship of mucosal bacterial communities that invade the inner mucus layer of the colon, known as biofilms, to sporadic and hereditary colon cancers will be discussed. Integration of new knowledge about the microbiota and colon cancer will inform current hypotheses on disease pathogenesis as well as future approaches to the prevention and possibly treatment of colon cancer.
Citation Format: Cynthia L. Sears. Biofilms, genetics, and colon cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA33.