bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5954: Germline epitopes modulate immune surveillance informing breast cancer subtypes
Authors: Houlahan Kathleen , Khan Aziz , Curtis Christina 
Published: April 2023

Abstract
Cancer represents a wide spectrum of molecularly and morphologically diverse diseases. Individuals with the same histopathological classification can have tumors with drastically different molecular profiles and clinical responses to treatment. It remains unclear as to when during the disease course these differences arise and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual’s germline genome, which can vary across millions of germline polymorphisms. It is unknown the extent to which germline differences influence the somatic evolution of a tumor. Interrogating 4,912 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in pre-invasive and invasive breast cancer. As a representative example, individuals with high burden of germline-derived epitopes in ERBB2 are significantly less likely to develop HER2+ breast cancer than ER+ or triple negative breast cancer. The same negative association between epitope burden and somatic amplification is observed for four recurrent amplicons observed in high risk ER+ breast tumors. No association was observed between somatic amplifications and epitope burden in metastatic breast cancer suggesting a subset of tumors are able to overcome immune-mediated negative selection. Tumors that do are more aggressive and demonstrate an “immune cold” phenotype. Taken together, these data show the germline genome plays a pivotal role in dictating somatic evolution in breast cancer. Exploiting germline-mediated immunoediting may facilitate the development of blood-based biomarkers that refine risk stratification within breast cancer subtypes.
Citation Format: Kathleen Houlahan, Aziz Khan, Christina Curtis. Germline epitopes modulate immune surveillance informing breast cancer subtypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5954.
Abstract 6755: The impact of renin-angiotensin system inhibitors on survival outcomes of pancreatic adenocarcinoma patients
Authors: Tseng Kuan-Yu , Chou Cheng-Wei 
Published: April 2023

Abstract
Introduction Pancreatic adenocarcinoma (PDAC) is a highly aggressive malignancy with significant morbidity and mortality. RAS (renin-angiotensin system) inhibitors have been used for hypertension, and the potential role of using RAS inhibitors in pancreatic adenocarcinoma have been investigated in pre-clinical models by enhancing drug delivery and reducing hypoxia. However, the clinical benefit of RAS inhibitors in pancreatic cancer patients was still unclear.
Methods We retrospectively investigated the impact of RAS inhibitors on survival outcomes of pancreatic adenocarcinoma patients in Taichung Veterans General Hospital between January 2014 and July 2021. Patients with histologically proven pancreatic adenocarcinoma were included in the study. Clinical feature with drugs exposure and survival outcome were analyzed.
Results A total of 384 pancreatic cancer patients were analyzed. Among them, 70 patients had concurrent use of RAS inhibitors and 314 patients had no concurrent medication use. Among patients with RAS inhibitors use, the diagnosed age was significantly older (70.0 vs. 68.0, p = 0.023), and a higher proportion of hypertension (100.0% vs. 51.0%, p &lt; 0.0001), chronic kidney disease (27.5% vs. 9.1%, p &lt; 0.0001), and diabetes (64.3% vs 39.5%, p &lt; 0.0001) than those without RAS inhibitors use. The 12-month progression-free survival were 22.9% and 13.7% in the RAS inhibitors and control group (p = 0.008), respectively. The Overall survival was not significantly different in the both groups (p = 0.356). In the multivariate analysis, the use of RAS inhibitors had a significantly better progression-free survival outcome (Hazard ratio = 0.025, CI:0.52-0.96). The advanced disease status, poor ECOG performance status and the elevated level of CA19-9 were correlated with poor progression-free survival.
Conclusion In our study, although higher percentage of existed comorbidities in the RAS inhibitor group, we demonstrated that the use of RAS inhibitors among pancreatic cancer patients might provide a better progression-free survival outcome. Further prospective study and investigation are warranted.
Citation Format: Kuan-Yu Tseng, Cheng-Wei Chou. The impact of renin-angiotensin system inhibitors on survival outcomes of pancreatic adenocarcinoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6755.
Abstract 676: Neuro-oncology imaging mass cytometry panels enable spatial investigation of brain tumor microenvironment
Authors: Zabinyakov Nick , Raza Qanber , Loh Christina 
Published: April 2023

Abstract
Brain neoplasms represent a complex form of cancer that is one of the most challenging to classify and treat. Over 120 different tumor subtypes originate from various parts of the central nervous system, which makes identifying the composition of the tumor microenvironment (TME) vital for early assessment of progression, treatment, and prevention. We developed high-plex proteomic analysis tools to thoroughly characterize the TME of both human and mouse brain tissues using Imaging Mass Cytometry™ (IMC™). IMC offers unprecedented insight into the TME by uncovering the spatial distribution of 40-plus distinct molecular markers without autofluorescence, facilitating the research of brain neoplasms. Here, we demonstrate the application of high-plex human and mouse neuro-oncology IMC panels on normal and tumor formalin-fixed paraffin-embedded brain tissues.
A basic neurophenotyping panel was developed and used to customize the Maxpar® Human and Maxpar OnDemand™ Mouse Immuno-Oncology IMC Panel Kits. Human and mouse neuro-oncology panels provide deep phenotyping and characterization of brain TME composition. These neuro panels consist of cross-reactive clones and enable flexible panel design for brain-specific research goals, such as brain tumor classification, and assessment of neuronal inflammation, degeneration, and development.
We applied the neuro-oncology panels on tissue microarrays (TMAs) containing a variety of human brain tumors and mouse glioblastoma and neuroblastoma tissues. Normal brain tissues were used for comparative analysis as controls. The Hyperion™ Imaging System was utilized to digitize images from the tissues followed by quantitative analysis to assess the cellular composition of normal and cancerous brain TME.
We successfully identified major cell populations that make up human and mouse brain matter, such as neurons, astrocytes, microglia, and oligodendrocytes. Various tumor cell phenotypes, resident and infiltrating cells, and resting and activated microglia were detected in multiple tumor subtypes. Subsequent single-cell analysis provided a comprehensive and quantitative assessment of the brain TME in our samples. We classified the distinct states of neurons and quantified myeloid and lymphoid immune cell infiltration across normal, astrocytoma, and glioblastoma tissues.
Empowered by high-plex neuro-oncology panels, IMC can accelerate brain tumor research and provide insights into the spatial complexity of neuronal neoplasms.
Citation Format: Nick Zabinyakov, Qanber Raza, Christina Loh. Neuro-oncology imaging mass cytometry panels enable spatial investigation of brain tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 676.
Abstract 68: Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution
Authors: Yoffe Liron , Borczuk Alain , McGraw Timothy E. , Elemento Olivier , Altorki Nasser K. , Mittal Vivek 
Published: April 2023

Abstract
Non-small cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide, largely due to diagnosis at advanced metastatic stages. Increased implementation of low-dose computed tomography (CT)-guided screening has led to the identification of non-solid lesions or ground-glass opacities (GGOs) that are not visible on plain chest radiography and can harbor very early-stage tumors. Growth of the lesions and/or development of a solid component can indicate more aggressive behavior. Using the low-dose CT reduced lung cancer mortality by &gt;20%, underscoring the need for early detection and intervention. However, the cellular and molecular determinants that contribute to the malignant progression of those early preinvasive lesions remain poorly understood. To assess intratumoral heterogeneity and associated dynamic changes in the immune contexture during early lung carcinogenesis, we performed single-cell RNA-seq and Hyperion imaging on surgically resected freshly harvested tissues from 21 patients (matched solid and non-solid components of lesions and adjacent non-involved lungs), representing a spectrum from preneoplasia to invasive disease. Analysis of &gt;300K cells identified cellular, transcriptomic, and metabolic alterations as well as tumor-stroma cross-talk pathways. Specifically, preinvasive to invasive disease progression was associated with significant changes in the immune landscape determined by an increase in exhausted CD4/CD8 T-cells, suppressive T-regs, polymorphonuclear myeloid-derived suppressor cells, and M2-like macrophages; and a decrease in cytotoxic CD8 T-cells, NK cells, and inflammatory cDC2 cells, suggesting that activation of immunosuppressive/anti-inflammatory microenvironment and suppression of immune activation microenvironment may enable tumor progression.
Citation Format: Liron Yoffe, Alain Borczuk, Timothy E. McGraw, Olivier Elemento, Nasser K. Altorki, Vivek Mittal. Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 68.
Abstract 693: A novel multi-subset dendritic cell vaccine derived from hematopoietic progenitor cells
Authors: Yu Chun , Barrett Richard L. , Zutshi Ananya , Palucka Karolina 
Published: April 2023

Abstract
Owing to their molecular features, tissue localization and antigen processing and presentation capacity, dendritic cells (DCs) induce and regulate T cell immunity including licensing T cells to kill target cells. However, tumors often suppress DC differentiation and function leaving cancer patients with DC populations that are quantitatively and qualitatively deficient. This limits both the native immune responses to tumors as well as response to cancer therapy including immunotherapy. Thus, provision of healthy and functionally intact DCs to replace and correct the in vivo function offers an interesting therapeutic opportunity. DCs are composed of multiple subsets which specialize in activation of different immune effectors. Thus, a combination of DC subsets could generate a broad and diverse immunity targeted at cancer. To date, several attempts have been made to generate functional human DCs ex vivo for injection to patients, but the DC subtypes most effective in generation of anti-tumor responses—cDC1 and cDC2s—have proven difficult to make ex vivo using clinically compliant protocols. Here we show that cDC1s and cDC2s can be generated at high yield from hematopoietic progenitor cells (HPCs) from three different HPCs sources (including adult bone marrow) using clinically compliant protocols. We characterize the phenotype and functionality of these cells showing that both cDC1s and cDC2s efficiently process antigens, stimulate, and expand T cells specific for those antigens, and that those T cell populations display targeted killing of tumor cells in vitro. The ability to produce these subtypes using clinically compliant protocols is a major step towards developing effective autologous DC therapy for cancer patients.
Citation Format: Chun Yu, Richard L. Barrett, Ananya Zutshi, Karolina Palucka. A novel multi-subset dendritic cell vaccine derived from hematopoietic progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 693.
Abstract 698: Developing a self-targeted cancer immunotherapy using engineered whole tumor cell-based vaccine
Authors: Chen Kok-Siong , Mendonca Natalia Claire , Borges Paulo , Shah Khalid 
Published: April 2023

Abstract
The administration of inactivated tumor cell lysate is known to induce a potent antitumor immune response, however, their therapeutic efficacy as shown in Phase I-III clinical trials is limited. This could be attributed to the lack of direct cytotoxic effect on tumor cells and the inability to trigger a strong antitumor immune response. Unlike inactivated tumor cells, living tumor cells possess a unique potential to home to and self-target tumors. Therefore, repurposing the tumor cells’ self-homing property and natural source of neoantigens is advantageous for self-targeted cancer immunotherapy. In this study, we developed a genetically engineered living whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles. We switched the tumor cells from death ligands sensitive to resistant using CRISPR/Cas9 and subsequently engineered them to release dual cell killing and immunomodulatory agents. These engineered therapeutic tumor cells (ThTC) eliminated established tumor and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTC translated into a marked survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompromised, immunocompetent and humanized mice. Arming naturally neoantigen-rich tumor cells with multidisciplinary therapeutics represents promising cell-based immunotherapy for solid tumors and establishes a roadmap towards clinical translation.
Citation Format: Kok-Siong Chen, Natalia Claire Mendonca, Paulo Borges, Khalid Shah. Developing a self-targeted cancer immunotherapy using engineered whole tumor cell-based vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 698.
Abstract 986: A BioPharma best practices framework to enable successful morphology guided spatial biology studies using NanoString GeoMx® Digital Spatial Profiler
Authors: Abad Leslie , McClain Maxine , Bonnevie Edward , Chen Benjamin , Church Sarah , Demirkan Gokhan , Haynes Premi , Hunter Kelly , Kersarwani Anil , Krull David , Liang Yan , Pal Prithwish , Ramos Corinne , Rodriguez Deniliz , Runyon Jessica , Tessier Julien , Anguiano Esperanza 
Published: April 2023

Abstract
The interest and utility of high-plex spatial profiling of RNA and protein biomarkers has increased over the last few years. The implementation of high-plex analyte spatial platforms, such as GeoMx® Digital Spatial Profiler (DSP), is increasing within discovery and development approaches for biomarkers associated with clinical outcome. The surge in spatial platforms parallels the increase of digital pathology in translational and clinical research studies. The integration of these two workflows has the potential to benefit diagnostic and therapeutic development. This study aims to facilitate the implementation of DSP in tissue analysis workflows helping those involved in drug discovery and development efforts to (1) assess platform feasibility for their research, (2) design effective DSP experiments, and (3) enable generation of high-quality, usable spatial data from large cohort studies. The BioPharma GeoMx DSP Consortium has developed consensus-based best practices incorporating the expertise of panel members via virtual meetings. Best practices guidelines for spatial profiling of tissue biopsies in drug discovery and development using GeoMx stands to advance current standard practices in tissue analysis. These best practices recommendations encompass every step of the implementation of DSP in standard tissue analysis workflows, emphasizing the importance of multidisciplinary stakeholder involvement, testing, defining experimental conditions prior to execution of large-scale studies, and considerations in assessing assay performance. This study offers a practical reference for the optimal implementation of GeoMx DSP in exploratory sample analysis for drug discovery and development studies.
Citation Format: Leslie Abad, Maxine McClain, Edward Bonnevie, Benjamin Chen, Sarah Church, Gokhan Demirkan, Premi Haynes, Kelly Hunter, Anil Kersarwani, David Krull, Yan Liang, Prithwish Pal, Corinne Ramos, Deniliz Rodriguez, Jessica Runyon, Julien Tessier, Esperanza Anguiano. A BioPharma best practices framework to enable successful morphology guided spatial biology studies using NanoString GeoMx® Digital Spatial Profiler [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 986.
Abstract 996: Identification of molecular biomarkers differentiating malignant uterine leiomyosarcoma from benign leiomyoma
Authors: Khamaiseh Sara , Koivisto-Korander Riitta , Ahvenainen Terhi , Bützow Ralf , Mehine Miika , Vahteristo Pia 
Published: April 2023

Abstract
Uterine leiomyosarcomas are rare, aggressive cancers that represent the most common type of uterine sarcomas. They frequently harbor genetic alterations in TP53, RB1, PTEN, and ATRX. Their benign counterpart, uterine leiomyomas (or fibroids) are very common tumors that may significantly affect women’s quality of life. The majority of leiomyomas harbor genetic alterations affecting either MED12, HMGA2, or FH. A third of leiomyosarcomas have been reported to harbor leiomyoma-associated driver mutations, suggesting that some leiomyomas may have undergone malignant transformation. The leiomyoma/leiomyosarcoma diagnosis is largely based on histopathology. This can be specifically challenging in differentiating leiomyosarcomas from a subset of leiomyomas that display histopathological features resembling malignancy. The aim of this study was to identify molecular biomarkers that can accurately differentiate benign and malignant uterine smooth muscle tumors. 3’RNA sequencing of 48 leiomyosarcomas and 44 leiomyomas revealed that leiomyosarcomas are uniquely characterized by dysregulation of the retinoblastoma pathway. We confirmed upregulation of several members of this pathway, including TOP2A and CDK1, in a publicly available transcriptomic dataset of 49 uterine leiomyosarcomas. The second objective of this study was to explore the gene expression profile of leiomyosarcomas carrying leiomyoma-associated driver mutations. This revealed that unlike leiomyomas, leiomyosarcomas do not form distinct gene expression profiles based on the presence of leiomyoma-associated driver mutations such as MED12. However, leiomyosarcomas with a MED12 mutation showed upregulation of RAD51B and ADAM12, which we have previously highlighted as biomarkers of leiomyomas harboring a MED12 mutation. We identified upregulation of IRS4 and characteristic deletions affecting COL4A5 and COL4A6 in four in-house and three additional uterine leiomyosarcomas from The Cancer Genome Atlas (TCGA) collection. Similar driver alterations have previously been reported in a small subset of leiomyomas but not in leiomyosarcomas. In conclusion, leiomyosarcomas display a gene expression profile characterized by dysregulation of genes related to the retinoblastoma pathway. These include potential biomarkers that could be used in a clinical setting to differentiate leiomyosarcomas from leiomyomas.
Citation Format: Sara Khamaiseh, Riitta Koivisto-Korander, Terhi Ahvenainen, Ralf Bützow, Miika Mehine, Pia Vahteristo. Identification of molecular biomarkers differentiating malignant uterine leiomyosarcoma from benign leiomyoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 996.
Abstract SY21-03: Organ-specific responses to targeted and immunotherapies
Authors: Sahai Erik 
Published: April 2023

Abstract
The response to treatment of widely disseminated disease can vary depending on the site of metastasis. In some cases, lesions at one site respond to treatment, while disease at other sites continues to grow. This is seen in the context of melanoma treatment with targeted therapy, with some patients having good responses in the liver, while disease in the brain and bone continues apace. This can be attributed to differences in the microenvironment of lesions in different organs, although other factors undoubtedly contribute. It is also increasingly clear that there is an interplay between the site of metastasis and responses to immunotherapy. Liver metastases are particularly difficult to treat compared to other metastatic locations. Moreover, the presence of liver metastases reduces the efficacy of immunotherapy to control disease at other sites in the same patient. Thus, liver metastases confer systemic tolerance. This is likely linked to the liver being a ‘tolerogenic’ organ with a role in modulating the body’s response to commensal bacteria in the gut. To investigate this, we have established an experimental melanoma model of systemic immune tolerance being conferred by liver metastases. We will present results on the mechanism by which liver metastases hinder not only their response to immunotherapy, but also the response of other distant lesions.
Citation Format: Erik Sahai. Organ-specific responses to targeted and immunotherapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY21-03.