bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B35: Studies on photo-sensitivity of a glycol porphyrin derivative and its anti-tumor efficacy
Authors: Vosahlikova Sarka , Moserova Irena Kusova , Kralova Jarmila , Reinis Milan , Mikyskova Romana , Fucikova Jitka Palich 
Published: June 2021

Abstract
Photodynamic therapy (PDT) has attracted great attention in cancer treatment. Porphyrin derivative with ethylene glycol chains linked to meta position of meso-tetraphenylporphyrin, mTPP(EG)4, is one of assumed compounds that can be used for treatment of cancer in photodynamic therapy (PDT). The aim of the study is to demonstrate the photodynamic efficacy in vitro and in vivo as well as to analyze its therapeutic mechanism. The cell viability, cell surface exposure of immunogenic molecules, maturation and phagocytic capacity of PDT-treated tumor cells were monitored by flow cytometry. The kinetics of key components of ER stress-mediated apoptotic pathway was analyzed by Western blotting. Our first results indicate a new and attractive possibility of immunogenic cell death induction. Initiation of immunogenic cell death by PDT was successfully demonstrated in vitro on human and mouse tumor cell lines. The effects of mTPP(EG)4 were compared with the effects of mTPP(EG)4 without subsequent photoactivation, hypericin-mediated PDT, and high hydrostatic pressure. In vivo assays evaluated immunogenicity of mTPP(EG)4 in mice and assessed the ability of PDT treated cells to induce effective immunity against transplanted syngeneic tumors (mouse TRAMP-C2, TC-1 and B16). The results obtained in this study will provide a basis for possible further preclinical experiments with mTPP(EG)4 or other derivatives, testing their potential in PDT and development of new antitumor therapies.
Citation Format: Sarka Vosahlikova, Irena Kusova Moserova, Jarmila Kralova, Milan Reinis, Romana Mikyskova, Jitka Palich Fucikova. Studies on photo-sensitivity of a glycol porphyrin derivative and its anti-tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B35.
Abstract B57: Integrating RNA expression and visual features for immune infiltrate prediction
Authors: Reiman Derek , Sha Lingdao , Ho Irvin , Tan Timothy , Lau Denise , Khan Aly A 
Published: June 2021

Abstract
Patient responses to cancer immunotherapy are shaped by their unique genomic landscape and tumor microenvironment. Clinical advances in immunotherapy are changing the treatment landscape by enhancing a patient’s immune response to eliminate cancer cells. While this provides potentially beneficial treatment options for many patients, only a minority of these patients respond to immunotherapy. In this work, we examined RNA-seq data and digital pathology images from individual patient tumors to more accurately characterize the tumor-immune microenvironment. Several studies implicate an inflamed microenvironment and increased percentage of tumor-infiltrating immune cells with better response to specific immunotherapies in certain cancer types. We developed NEXT (Neural-based models for integrating gene EXpression and visual Texture features) to more accurately model immune infiltration in solid tumors. To demonstrate the utility of the NEXT framework, we predicted immune infiltrates across four different cancer types and evaluated our predictions against expert pathology review. Our analyses demonstrate that integration of imaging features improves prediction of the immune infiltrate. Of note, this effect was preferentially observed for natural killer, macrophage, and CD8 T cells. In sum, our work effectively integrates both RNA-seq and imaging data in a clinical setting and provides a more reliable and accurate prediction of the immune composition in individual patient tumors.
Citation Format: Derek Reiman, Lingdao Sha, Irvin Ho, Timothy Tan, Denise Lau, Aly A Khan. Integrating RNA expression and visual features for immune infiltrate prediction [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B57.
Abstract B59: Co-evolution between tumor cells and immune system in the setting of T-cell immunotherapy
Authors: George Jason T. , Garber Haven R. , Molldrem Jeffrey J. , Levine Herbert 
Published: June 2021

Abstract
It is now well established that the host’s adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. However, tumor acquisition of immune evasive phenotypes, such as class-I MHC downregulation, remains a major limitation of successful T-cell immunotherapy. We propose a stochastic model that couples tumor and CD8+ T-cell adaptive immune compartments. This framework accurately models relevant empirical findings, including the growth-threshold conjecture of immune activation, and predicts experimental observations including “sneak-through,” wherein intermediate-growth threats are penalized relative to their slower- and faster-growing counterparts. We demonstrate that predicted optimal growth strategies depend on whether or not the threat may acquire an immune-evasive phenotype as well as the mode of immune detection. The model is able to accurately characterize age-dependent cancer incidence data as a function of decreasing T-cell turnover and repertoire diversity. Lastly, we quantify therapeutic efficacy of immunotherapy in the setting of an immune-evasive threat. Our model serves as a first attempt at modeling stochastic cancer evolution sculpted by an adaptive immune compartment.
Citation Format: Jason T. George, Haven R. Garber, Jeffrey J. Molldrem, Herbert Levine. Co-evolution between tumor cells and immune system in the setting of T-cell immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B59.
Abstract B68: Pre-existing immune memory to cancer-associated phosphopeptides in healthy donors
Authors: Lulu Amanda M. , Cummings Kara L. , Engelhard Victor H. 
Published: June 2021

Abstract
Identifying appropriate antigens is essential to developing effective cancer vaccines. Protein phosphorylation plays a major role in signal transduction pathways that are dysregulated and contribute to the malignant phenotype of cancer cells. Our lab has shown that phosphopeptides derived from these proteins can be presented by major histocompatibility complex Class-I molecules and represent a new class of cancer-associated neoantigens. We previously reported that healthy donors without evident prior cancer had unusually robust CD8 T-cell responses to a cohort of HLA-B7+ leukemia-associated phosphopeptides, suggesting that they might be due to pre-existing phosphopeptide specific memory T cells. To test this, we evaluated CD8+CD45RO+ memory T cells purified from the blood of healthy donors. These cells showed robust responses to 2-25% of HLA-A2+ and 0-23% of HLA-B7+ cancer-associated phosphopeptides. This demonstrates that healthy individuals with no evident cancer history have pre-existing immune memory to some cancer-associated phosphopeptides. We identified 3 “immunodominant” HLA-A2 associated phosphopeptides, in that memory responses were evident to them in the majority of analyzed donors. Such immunodominance suggests that these phosphopeptides result from signaling processes that occur commonly in transformation- or viral infection-related processes. In contrast, immunodominant phosphopeptides were not evident in the context of HLA-B7. While 2 donors showed pre-existing immune memory to a large number of shared targets, other donors showed memory to only small numbers of nonoverlapping phosphopeptides. This suggests that the mechanisms driving expression of these phosphopeptide antigens among healthy donors are much less common. We also found that responses to some phosphopeptides could be detected directly ex vivo. In some cases, the phosphopeptide targets of these ex vivo responses did not stimulate responses after 2 weeks in culture. These results suggest that some phosphopeptides in some donors may be the targets of ongoing immune responses composed of effector or effector memory cells that do not persist long-term in culture. These results provide evidence of regular, ongoing immune surveillance in healthy individuals to cancer-associated phosphopeptides.
Citation Format: Amanda M. Lulu, Kara L. Cummings, Victor H. Engelhard. Pre-existing immune memory to cancer-associated phosphopeptides in healthy donors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B68.
Abstract IA10: Metabolic regulation of cell proliferation
Authors: Vander Heiden Matthew G. 
Published: June 2021

Abstract
Complex regulatory mechanisms enable cell metabolism to match physiologic state. The major pathways cells use to turn nutrients into energy and to synthesize macromolecules have been elucidated; however, there remain many unanswered questions regarding how metabolism supports cell proliferation and how this varies in different cell types in both normal and disease states. We have found that acquisition of some amino acids, including aspartate and serine, can be limiting for cell proliferation and that both environmental and cell lineage factors can influence how cells obtain critical nutrients for proliferation. How metabolism influences tumor growth will be discussed, including how cancer cells and immune cells might compete for limiting nutrients.
Citation Format: Matthew G. Vander Heiden. Metabolic regulation of cell proliferation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA10.
Abstract IA15: Vascular reprogramming for enhancing cancer immunotherapy
Authors: De Palma Michele 
Published: June 2021

Abstract
Immune checkpoint blockade can reinvigorate the tumor-antagonizing functions of T cells and be potentially curative, but the majority of the tumors are either refractory or become resistant to the treatment. Among various parameters, the lack of pre-existing T-cell infiltrates may determine tumor refractoriness to immune checkpoint blockade and other cancer immunotherapies. Increasing data indicate that angiogenic blood vessels can limit the infiltration and functionality of T cells in tumors. For example, high intratumoral VEGFA levels make the tumor blood vessels dysfunctional and poorly permissive to T-cell extravasation, in part through the downregulation of T-cell adhesion molecules on the vascular endothelium. Besides VEGFA, angiopoietin-2 (ANGPT2) also induces abnormal tumor angiogenesis. Accordingly, combined blockade of VEGFA and ANGPT2 reprograms the tumor blood vessels to a form that is conducive to improved T-cell activation and trafficking and enhances tumor response to both immune checkpoint blockade (anti-PD-1) and agonistic CD40 antibodies in several genetically defined mouse cancer models. In my lecture I will discuss the applications, prospects, and current limitations of antiangiogenic immunotherapies.
Citation Format: Michele De Palma. Vascular reprogramming for enhancing cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA15.
Abstract IA22: Pharmacologic and physiologic processes that affect response to immunotherapy
Authors: McAllister Sandra S. 
Published: June 2021

Abstract
Immune checkpoint blockade therapy has revolutionized the treatment of many cancer types and has proven effective for ~10-20% of breast cancer patients in early clinical trials. For patients with triple-negative breast cancer, these responses represent an improvement over standard therapeutic strategies, offering hope that improving efficacy of immunotherapies will save patient lives. However, the reasons for resistance or lack of response to these therapies in breast cancer are unknown. First, we made preclinical observations that provide rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anticancer treatment. Using various preclinical breast cancer models, we showed that selective CDK4/6 inhibitors cause tumor regression by promoting antitumor immune responses. Genome-wide expression data from patient tumors in the NeoPalAna trial revealed similar antitumor immune signatures. The antitumor immunity occurs through processes that affect both tumor cells and the immune microenvironment. Hence, disease regression was further enhanced using a combination therapy regimen comprising a CDK4/6 inhibitor with immune checkpoint blockade. Second, we found that age-related changes to immune function present limitations to the application of immunotherapy in our triple-negative breast cancer (TNBC) preclinical models. While TNBC incidence is similar in young and old patients, it is not known whether age impacts response to immunotherapy in breast cancer. In fact, while over 50% of patients are over 65 years of age at diagnosis, elderly individuals are often excluded from clinical trials for various reasons. We found that aged mice (&gt;12 months, corresponding to ~65-year old humans) had significantly reduced ability to respond to either anti-PD-L1 or anti-CTLA4 compared to young counterparts (8-10 weeks, corresponding to ~25-year old humans). Using high-content flow cytometric analyses and RNA-seq, we identified cellular and molecular mechanisms that correlate with response in young mice that are attenuated in old mice. Many of the differentially expressed genes that defined response in the young cohorts and resistance in the older cohorts were also predictors of response to immunotherapy in cancer patients. Our data suggested novel combination therapies that, when combined with checkpoint blockade, improved responses and survival in the old TNBC cohort. By studying pharmacologic and physiologic processes that improve responses, we hope to suggest new treatment strategies that ensure that breast cancer patients see the most benefit possible from checkpoint blockade therapy.
Citation Format: Sandra S. McAllister. Pharmacologic and physiologic processes that affect response to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA22.
Abstract PR10: Heterogenous activation of multiple suppressive pathways by scRNAseq may underscore resistance to PD-1 therapy in metastatic castration-resistant prostate cancer
Authors: Wang Chaojie , Graff Julie , Xia Zheng , Moran Amy 
Published: June 2021

Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease that, until recently, was thought to be resistant to checkpoint blockade. A recent clinical trial revealed that the PD-1 inhibitor, pembrolizumab, when given in combination with the androgen-deprivation therapy (ADT) drug enzalutamide, achieved an unprecedented 18% complete biochemical response rate in mCRPC patients. Though promising, ~80% of these patients failed to respond and the mechanisms of resistance remain unclear. The immunologic landscape of mCRPC is largely unknown. We hypothesize that mechanisms of resistance to anti-PD-1 therapy may reflect the heterogeneity of immune suppression in this disease. Revealing this heterogeneity is difficult to achieve because access to the metastatic disease is limited to core-needle biopsies of largely bone and lymph node disease. Therefore, to reveal pathways of resistance, we developed a protocol for isolating leukocytes and performing single-cell RNAseq from fresh core-needle biopsies taken from enzalutamide-resistant metastatic lesions prior to and after pembrolizumab treatment. The abundance of tumor-infiltrating leukocytes was on average less than 1% of total cells independent of biopsy location. Using our single-cell RNA sequencing data, we generated a leukocyte gene signature of enzalutamide mCRPC and used this to retrospectively deconvolute bulk RNA sequencing data from a cohort of 16 paired biopsies from enzalutamide-naive and -resistant patients. Computational approaches revealed the diverse leukocyte heterogeneity of mCRPC and multiple suppressive pathways beyond PD-1 within the tumor microenvironment. Importantly, the suppressive pathways were shared between metastatic biopsy locations (i.e., bone vs lymph node). To validate these targets in combination with ADT treatment, we developed orthotopic mouse models of mCRPC in immunocompetent mice. These strategies will identify new opportunities for clinical intervention to enhance antitumor responses in this patient population.
This abstract is also being presented as Poster A04.
Citation Format: Chaojie Wang, Julie Graff, Zheng Xia, Amy Moran. Heterogenous activation of multiple suppressive pathways by scRNAseq may underscore resistance to PD-1 therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR10.
Abstract PR20: A novel combination immunotherapy with a vaccine targeting tumor neoepitopes that mediates immune cascade in murine tumor models
Authors: Lee Karin L. , Palena Claudia , Lee John , Niazi Kayvan , Nguyen Andrew , Jones Frank , Rabizadeh Shahrooz , Soon-Shiong Patrick , Schlom Jeffrey , Hamilton Duane H. 
Published: June 2021

Abstract
Clinical successes utilizing checkpoint inhibitors demonstrate the potential of immune-based therapies for the treatment of cancer. Research suggests that these successes are a result of T cells recognizing nonsynonymous mutations uniquely expressed by a patient’s tumor. The advent of comparative tumor-normal DNA sequencing and tumor RNA sequencing for accurate prediction of presented somatic mutations has made it possible to rapidly identify these neoepitopes, allowing for the development of personalized cancer vaccines. However, such vaccines are often ineffective due to the immunosuppressive nature of the tumor microenvironment, and their clinical efficacies would be improved when used in an orchestrated combination approach with additional immune-oncology agents. In the present study, we investigated the combination of three immune-oncology agents, each targeting a unique mechanism of immune therapy, with a vaccine targeting tumor neoepitopes. We combined a neoepitope vaccine, delivered as a peptide or via a novel E2b-deleted adenovirus vehicle, with N-IL15 (previously called ALT-803), an IL-15 superagonist, to enhance the development of antigen-specific immunity; NHS-IL12, a tumor-targeting IL-12 molecule, to promote the maintenance and expansion of T cells within the tumor microenvironment; and PD-L1 blockade to decrease immune cell exhaustion within the tumor microenvironment. This combination therapy resulted in the regression of established tumors, which associated with the generation of robust immunity against neoepitopes contained in the vaccine. It also showed evidence of inducing a neoepitope cascade by causing development of T-cell responses to neoepitopes expressed by the tumor but not contained within the vaccine. This report is the first demonstration of an E2b-deleted adenovirus neoantigen vaccine generating robust immunity. Together, this study demonstrates the importance of a multifaceted, orchestrated treatment regimen to promote the generation of effective antitumor immunity.
This abstract is also being presented as Poster A18.
Citation Format: Karin L. Lee, Claudia Palena, John Lee, Kayvan Niazi, Andrew Nguyen, Frank Jones, Shahrooz Rabizadeh, Patrick Soon-Shiong, Jeffrey Schlom, Duane H. Hamilton. A novel combination immunotherapy with a vaccine targeting tumor neoepitopes that mediates immune cascade in murine tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR20.
Turismo Cultural y Policy Network: caracterización del modelo de negocio en la comuna de Camarones, Región de Arica y Parinacota, Chile
Authors: Acevedo-Mora Carlos 
Published: June 2021

El presente artículo expone loa hallazgos una investigación destinada a estudiar la situación de la actividad turística cultural desde la perspectiva de los modelos de negocio de la red empresarial de la comuna de Camarones. Para tales efectos se exponen las distinciones del turismo cultural y sus variantes que son posibles de desarrollar en este territorio, así como también los conceptos modelos de negocios y sus componentes. La metodología de investigación empleada fue de tipo exploratorio cualitativo y las categorías de análisis se construyeron con base a las variables del modelo de negocios Canvas.

Palabras clave: Red empresarial, Turismo Cultural, modelo de negocio, Bussines Model Canvas, comuna de Camarones-Chile
Activation of the Central Renin-Angiotensin System Causes Local Cerebrovascular Dysfunction
Authors: De Silva T. Michael , Modrick Mary L. , Grobe Justin L. , Faraci Frank M. 
Published: June 2021

Background and Purpose:
Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension, its potential impact on the local vasculature is unclear. We tested the hypothesis that activation of the brain RAS would alter the local vasculature using a modified deoxycorticosterone acetate (DOCA) model.

Methods:

C57BL/6 mice treated with DOCA (50 mg SQ; or shams) were given tap H
2
O and H
2
O with 0.9% NaCl for 1 to 3 weeks.

Results:

In isolated cerebral arteries and parenchymal arterioles from DOCA-treated male mice, endothelium- and nitric oxide-dependent dilation was progressively impaired, while mesenteric arteries were unaffected. In contrast, cerebral endothelial function was not significantly affected in female mice treated with DOCA. In males, mRNA expression of renal
Ren1
was markedly reduced while RAS components (eg,
Agt
and
Ace
) were increased in both brain and cerebral arteries with central RAS activation. In NZ44 reporter mice expressing GFP (green fluorescent protein) driven by the angiotensin II type 1A receptor (
Agtr1a
) promoter, DOCA increased GFP expression ≈3-fold in cerebral arteries. Impaired endothelial responses were restored to normal by losartan, an AT1R (angiotensin II type 1 receptor) antagonist. Last, DOCA treatment produced inward remodeling of parenchymal arterioles.

Conclusions:
These findings suggest activation of the central and cerebrovascular RAS impairs endothelial (nitric oxide dependent) signaling in brain through expression and activation of AT1R and sex-dependent effects. The central RAS may be a key contributor to vascular dysfunction in brain in a preclinical (low renin) model of hypertension. Because the brain RAS is also activated during aging and other diseases, a common mechanism may promote loss of endothelial and brain health despite diverse cause.