bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5571: FoxP3 absolute quantification to build an effective risk model for cancer patient survival
Authors: Ponzoni Adele , Delebecq Sandra , Boute Melodie , Ramos Corinne , Stauber Jonathan 
Published: April 2023

Abstract
Background: Forkhead box protein P3 (FOXP3), belonging to the forkhead/winged-helix family, is of great importance in modulating the differentiation and development of T-regulatory cells (Tregs). The numbers of FOXP3+ Tregs as well as exhaustive subsets of CD4+ and CD8+ T cells have been observed increased in solid tumor tissues of patients with colorectal and breast cancers, which helps to create an immunosuppressive environment and promotes tumor progression. However, the correlation between the presence of FOXP3+ Tregs and patients’ survival has been extensively studied in many cancer types, which remains conflicting. The approach presented here aims to absolutely quantify the level of FOXP3 in single cells and constructed effective immune risk models to predict tumor prognosis.
Method: Imaging mass cytometry (IMC) was used to quantify FOXP3 inside each single cell. The indirect quantification used a free-metal titration curve in order to match the level of intensity of the metal-tagged antibodies to the level of expression of the antigen. Deep learning (StarDist QuPath extension) was used for cell segmentation and expression quantification. FOXP3 quantification in tissue or at the single cell level was validated against ELISA assay that measure FOXP3 in tissue lysate.
Results: Linearity of the metal signals with an average %CV of 17% was observed emphasizing the linear correlation between free metal concentration and intensity. With the IMC technique, the minimum amount of FoxP3 detectable is 0.09 femtogram and its absolute quantification in the different cells in tumor tissues was confronted to disease prognosis in order to start building an effective immune risk model.
Conclusion: With the introduction of new biologics in cancer therapy, it is imperative to follow real quantitative change in the expression of biological marker that are indicator of tumor prognosis. Indeed, although the FOXP3 distribution was already seen to be heterogenous in tumors, its absolute level of expression indicative of disease progression can be directly correlated to gain better understanding of the patient response stratification to biologics.
Citation Format: Adele Ponzoni, Sandra Delebecq, Melodie Boute, Corinne Ramos, Jonathan Stauber. FoxP3 absolute quantification to build an effective risk model for cancer patient survival. [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 5571.
Abstract 5666: NAV-003, a full-length IgG1 bispecific antibody targeting a unique mesothelin epitope and CD3 to improve cytotoxicity against humoral immunosuppressed tumors
Authors: Grasso Luigi , Jiang Qun , Hassan Raffit , Nicolaides Nicholas C. , Kline J. Bradford 
Published: April 2023

Abstract
Mesothelin (MSLN) is a cell surface protein over-expressed in a number of cancer types. Several antibody- and cellular-based MSLN targeting agents have been tested in clinical trials where their therapeutic efficacy has been moderate at best. Previous studies using antibody and CAR-T based agents have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found certain MSLN-positive tumors can produce proteins that can bind to subsets of IgG1-type antibodies and suppress their immune-effector activities. In an attempt to develop a more optimized anti-MSLN targeting agent, we engineered a humanized divalent anti-MSLN/anti-CD3ε bispecific antibody called NAV-003 that targets a MSLN epitope proximal to the tumor cell surface and an anti-CD3ε single-chain antibody capable of effectively binding, activating and directing T-cells to the surface of MSLN-bound tumor cells. NAV-003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV-003 demonstrated good tolerability and efficacy against patient-derived mesothelioma xenograft models co-engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV-003 clinical development and human proof-of-concept studies in patients with MSLN-expressing cancers.
Citation Format: Luigi Grasso, Qun Jiang, Raffit Hassan, Nicholas C. Nicolaides, J. Bradford Kline. NAV-003, a full-length IgG1 bispecific antibody targeting a unique mesothelin epitope and CD3 to improve cytotoxicity against humoral immunosuppressed tumors. [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 5666.
Abstract 5818: Cadherin complexes recruit PIWIL2 to suppress pro-tumorigenic transformation
Authors: Risner Alyssa , Nair-Menon Joyce , Gangaraju Vamsi , Kourtidis Antonis 
Published: April 2023

Abstract
Recent studies have shown that genomic instability, oncogene expression, and high mutation rates in more than 50% of tumors can be attributed to increased transposon activity. Transposons, also called transposable elements (TEs), are parasitic mobile DNA elements that make up 45% of the human genome and can cause DNA damage and gene mutations. The reasons for increased TE activity in somatic tumors are currently unknown. TE RNA transcripts are targeted for degradation by PIWI ribonucleases, which are members of the Argonaute superfamily of proteins, through regulation of small RNAs called piRNAs (PIWI-interacting RNAs). Although the function of the PIWI-piRNA pathway has been extensively studied in the germline, there is little understanding about the presence or functionality of the pathway in somatic tissues. We have evidence of a novel interaction of the adherens junctions of well-differentiated epithelial cells with PIWIL2 (PIWI-like RNA-Mediated Gene Silencing 2), a key catalytic component of the PIWI-piRNA complex. Through immunofluorescence staining, confocal microscopy, and co-immunoprecipitation studies, we found co-localization and association of PIWIL2, as well as of other key members of the PIWI complex, such as PIWIL4 and TDRD1, with E-cadherin and p120 catenin at adherens junctions of well-differentiated breast and colon epithelial cells, whereas this association is lost in cancer cells and patient tissues. Adherens junction disruption results in mis-localization of PIWIL2, PIWIL4, and TDRD1 from the adherens junctions and their accumulation either to the cytoplasm or to the nucleus. E-cadherin depletion particularly results in increased expression of the LINE1 transposon, which is the most abundant transposon in human cells, and in increased levels of γ-H2AX, an indicator of DNA damage. Our working hypothesis is that cadherin junctions of well-differentiated epithelial cells recruit and regulate the PIWIL2 complex to suppress transposon activity. Since both loss of junctional integrity and increased transposon activity are universal events in cancer, this study has the potential to deepen our understanding of the role of the PIWI-transposon pathway in somatic tumorigenesis.
Citation Format: Alyssa Risner, Joyce Nair-Menon, Vamsi Gangaraju, Antonis Kourtidis. Cadherin complexes recruit PIWIL2 to suppress pro-tumorigenic transformation [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 5818.
Abstract 5819: Src inhibitor suppresses rab11 mediated collective cell migration in colon cancer cells
Authors: Lu Yi-Wen , Hou Xiang-Ling , Koo Hui Min , Chao Wei-Ting 
Published: April 2023

Abstract
Collective cell migration has been demonstrated the importance in cancer metastasis. Instead of single cell migration, collective cell migration requires E-cadherin for the cohort cell migration. Rab11 the recycling vesicle protein plays the key role in E-cadherin dynamics and mediates collective cell migration. In this study, Src was hypothesized to regulate Rab11 mediated collective cell migration. Our results demonstrated Src inhibitor Dasatinib has less toxicity in HT-29 colon cancer cells, instead, the cell morphology was turned aggregated. The immunofluorescence image also showed E-cadherin polarity was lost after Dasatinib treatment and increased the potential of cell-cell contact inhibition. In transwell assay, Rab11 was found colocalized with E-cadherin in collective migrated cells. Dasatinib treatment can suppress collective cell migration and decrease the interaction of Rab11 and E-cadherin. This study demonstrated the important role of Src in Rab11 mediated collective cell migration through E-cadherin dynamics in colon cancer.
Citation Format: Yi-Wen Lu, Xiang-Ling Hou, Hui Min Koo, Wei-Ting Chao. Src inhibitor suppresses rab11 mediated collective cell migration in colon cancer 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 5819.
Abstract 5902: The immune features of Helicobactor pylori-positive gastric cancer provides insights into immunotherapy
Authors: Jia Keren , Chen Yang , Chong Xiaoyi , Li Yilin , Yuan Jiajia , Li Yanyan , Zhang Xiaotian , Li Jian , Shen Lin 
Published: April 2023

Abstract
Introduction: Helicobactoer pylori (H. pylori) is one of the most important risk factors of gastric cancer (GC). However, the effects of Helicobacter pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses is still lacking.
Methods: We included 61 patients, 46 of whom received anti-PD-1/PD-L1 based immunotherapy. Patients’ samples at baseline were collected and examined with multiplex immunothistochemistry. Four detecting panels including 16 kinds of antibodies were used to label CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils, and their functional status. Immunotherapy-related overall survival (irOS) is the interval from the initiation of immunotherapy to death or the last following up. mmunotherapy-related progression-free survival (irPFS) is the interval from the initiation of immunotherapy to disease progression or the last following up. The Student’s t test is used to compared the average density of immune cells. The Chi-squared test was used to compare the objective response rate (ORR) between two groups.
Results: H. pylori-positive rate was 29/61. In 46 patients received immunotherapy, 23 patients were infected with H. pylori. There was a increasing trend for the density of CD8+ T cells, B cells, and neutrophils in H. pylori-positive patients compared with negative group.
We observed that the densities of total CD4+ T cells, CD4+PD-L1+, and CD4+CTLA-4+ T cells, were higher in H. pylori-positive group compared with negative group (522.58 vs. 268.77/mm^2, P=0.020, 118.94 vs. 265.98/mm^2, P=0.0091; 61.30 vs. 18.56/mm^2, P=0.035). In addition, STING positive macrophages (CD68+STING+ cells) were also enriched in H. pylori-positive group than negative group (138.45 vs. 44.15/mm^2, P=0.0012).
Next, we found H. pylori-positive patients harbored higher ORR than negative group (47.62% vs. 17.39%, P=0.032). However, there were no significant difference of irPFS and irOS between positive and negative group (median irPFS: 5.97 vs. 6.83 months, hazard ratio: 1.02, P=0.96; median irOS: 12.83 vs. 10.97 months, hazard ratio: 0.855, P=0.59).
Conclusions: We observed the enrichment of total CD4+ T cells, CD4+PD-L1+ T cells, CD4+CTLA-4+ T cells, and CD68+STING+ cells in H. pylori-positive patients, indicating the combination of anti-CTLA-4 or STING may enhance the efficacy of immunotherapy in H. pylori-positive GC.
Citation Format: Keren Jia, Yang Chen, Xiaoyi Chong, Yilin Li, Jiajia Yuan, Yanyan Li, Xiaotian Zhang, Jian Li, Lin Shen. The immune features of Helicobactor pylori-positive gastric cancer provides insights into immunotherapy. [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 5902.
Abstract 5912: Bitter taste receptors link between microbiome dysbiosis and programmed cell death in oral squamous cell carcinoma
Authors: Hwang Byeong-Oh , Park Se-Young , Song Na-Young 
Published: April 2023

Abstract
Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancers. It has been reported that the composition of the oral microbiome was shifted in OSCC patients compared to healthy subjects. In particular, Pseudomonas aeruginosa was enriched in the oral cavity of OSCC patients. Bitter taste receptors (taste 2 receptors, TAS2Rs), known as G protein-coupled receptors (GPCRs), can recognize quorum sensing molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12) secreted from P. aeruginosa. Based on The Cancer Genome Atlas analysis, downregulation of TAS2Rs was correlated with poor prognosis in various cancers. This prompted us to investigate the role of TAS2Rs in oral dysbiosis and cancers. Here, we found that TAS2Rs mediated both apoptosis and pyroptosis, distinct types of programmed cell death, in response to oxo-C12, in OSCC cell lines. Of note, it was blocked by knockdown of TAS2R4, 14, or 38. Unexpectedly, TAS2Rs-mediated apoptosis and pyroptosis were GPCR-independent. Given our observation that the blockade of NLRP3 inflammasome attenuated oxo-C12-induced OSCC cell death, TAS2Rs seem to recruit NLRP3 inflammasome rather than G protein signaling pathway in order to mediate the programmed cell death in OSCC. Once NLRP3 is activated, caspase-8 triggered both apoptosis and pyroptosis in response to oxo-C12, supporting the role of TAS2Rs-NLRP3-caspase-8 axis. Interestingly, siRNA knockdown of MyD88 diminished oxo-C12-induced programmed cell death, implying the possible involvement of MyD88 in the TAS2Rs-NLRP3-caspase-8 axis. Taken together, bitter taste receptors promote the programmed cell death of OSCC in response to oral dysbiosis through activation of NLRP3 inflammasome, which further supports TAS2Rs as prognostic markers in OSCC. Thus, these results will shed light on better understanding of interplay between microbiome and cancer, proposing TAS2Rs as novel therapeutic targets in oral dysbiosis-induced OSCC development.
Citation Format: Byeong-Oh Hwang, Se-Young Park, Na-Young Song. Bitter taste receptors link between microbiome dysbiosis and programmed cell death in oral squamous cell carcinoma [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 5912.
Abstract 5917: Development of a medium-to-high throughput organoid-bacteria co-culture platform for the assessment of host pathogen interaction
Authors: Valle-Encinas Eider , Nair Roshni , Pisa Katerina , Doorn Mayke , Pourfarzad Farzin , Mateo Lani San , Desch Nicole , Gokare Prashanth , Pocalyko David , Boj Sylvia F. , Verissimo Carla 
Published: April 2023

Abstract
Pathogens such as colibactin-producing bacteria strains of the Enterobacteriaceae family are highly prevalent in the gut microbiota of colorectal cancer (CRC) patients. HUB patient derived Organoids, (HUB-OrganoidsTM or PDOs) are self-organized epithelial cell structures with near-physiological features, extensively used to model aspects of cancer initiation and progression. Studies conducted by Pleguezuelos-Manzanos et al. (2020) showed that repetitive cycles of colibactin-producing bacteria into the organoid lumen via microinjection, led to two co-occurring mutational signatures appearance, a single-base substitution signature (SBS-pks) and an indel signature (ID-pks), identified in a subset of CRC patients (~2% and 7%, respectively). These results highlight the relevance of organoids for modelling host-pathogen interactions and the application of these systems as in vitro platforms for investigating long-standing cause-correlation relationship between the presence of genotoxic pathogens and CRC development. The limited scalability of sophisticated co-culture strategies with pathogens such as microinjection has represented a bottleneck in the use of organoids as throughput screening tools in the development of preventive therapies. Thus, there is an unmet need to develop alternative co-culture systems compatible with the process of compound screening. An organoid-bacteria co-culture system compatible with medium-to-high throughput screening readouts has been developed. This co-culture system is currently tailored for the modeling of colibactin genotoxic effects in the gut epithelium, but theoretically could be extended as a discovery platform to identify targetable, novel and complex interactions between host and pathogen. Key words: colibactin, organoids, CRC, screening
Citation Format: Eider Valle-Encinas, Roshni Nair, Katerina Pisa, Mayke Doorn, Farzin Pourfarzad, Lani San Mateo, Nicole Desch, Prashanth Gokare, David Pocalyko, Sylvia F. Boj, Carla Verissimo. Development of a medium-to-high throughput organoid-bacteria co-culture platform for the assessment of host pathogen interaction [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 5917.
Abstract 5923: The genetic landscape of metastatic breast cancer reflected in circulating tumor DNA
Authors: Kavan Stephanie 
Published: April 2023

Abstract
Tissue biopsies of breast tumors only provide a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. Plasma-derived cell-free tumor DNA constitutes a potential surrogate for tumor DNA obtained from tissue biopsies to potentially capture inter-and intra-tumoral heterogeneity present in metastatic breast cancer. We aimed to investigate to what extent variants identified in the primary tumor and metastases are reflected in plasma. We performed whole-exome sequencing on tumor DNA from primary and metastatic lesions and plasma-derived circulating tumor DNA of eight patients with metastatic breast cancer. Our results show that metastases most often follow parallel evolution, given the low levels of stem mutations detected between primary tumors and matched metastases and mutational events private to the primary tumor. Furthermore, we demonstrated that ctDNA mainly reflected old stem mutations shared between primary tumor and metastasis, and less often, genetic alterations found solely in primary tumor or metastasis. Lastly, clinically relevant variants, e.g., resistance mutations detected in primary tumor and metastasis, were to some extent reflected in ctDNA, including affected genes MET, MTOR, CDK6, PIK3CA, and GATA3. However, mutations in MED1, NCOR1, and NCOR2 were only found in tumor tissues. These findings support the importance of a metastatic deposit biopsy to guide treatment decisions. Together, our results have implications for future ctDNA studies. For monitoring tumor burden using ctDNA, our results suggest that truncal mutations are the best candidates, as they are highest in circulating levels. For confident tracking of subclonal mutations in ctDNA, liquid biopsies are not yet to substitute metastatic tissue biopsies and instead demonstrate support to the current gold standard.
Citation Format: Stephanie Kavan. The genetic landscape of metastatic breast cancer reflected in circulating tumor DNA [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 5923.
Abstract 5950: Ccr2+ monocyte derived macrophages influence trajectories of acquired therapy resistance in BRAF-mutant melanoma
Authors: Kim Dahihm , An Luye , Moon Jiwon , White Andrew 
Published: April 2023

Abstract
Therapies targeting oncogene addiction have had a tremendous impact on patient care, but drug resistance continues to be problematic. One method to deal with this challenge entails extending the scope of anti-cancer treatment beyond tumor cells by additionally altering their tumor microenvironment. Understanding how the tumor microenvironment can contribute to the evolution of diverse resistance pathways could aid in the rational design of sequential treatments that enforce pressure towards a more predictable resistance trajectory. Tumor associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models and Ccr2-RFP; Cx3cr1-GFP mice to track the long-term changes in tumor cells and macrophages under targeted therapy with Braf/Mek inhibitors. We assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ macrophage infiltration rises, underscoring a prominent role at this point in melanoma evolution for development of drug-resistance. Importantly, we show that a lack of melanoma infiltrating Ccr2+ macrophages delays onset of resistance. In this case, rebounded tumor cells from Ccr2 knockout recipients favor the evolution of cell-extrinsic mediated resistance mechanisms, which can be reversed when these adapted melanoma cells are relocated to a microenvironment with functional Ccr2. Conversely, Ccr2 presence promotes development of cell-intrinsic drug resistance with a stable phenotype in rebounded tumor cells. Overall, this demonstrates that the development of resistance may be manipulated and directed to improve timing and probability of relapse.
Citation Format: Dahihm Kim, Luye An, Jiwon Moon, Andrew White. Ccr2+ monocyte derived macrophages influence trajectories of acquired therapy resistance in BRAF-mutant melanoma. [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 5950.