bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 65: Differential impacts of PD-L1 expression in tumor vs. stroma on survival in esophageal squamous cell carcinoma
Authors: Murakami Tomohiro , Furuhashi Satoru , Sakai Yuuki , Sekimori Kenichi , Haneda Ryoma , Booka Eisuke , Matsumoto Tomohiro , Kikuchi Hirotoshi , Hiramatsu Yoshihiro , Takeuchi Hiroya 
Published: March 2024

Abstract
Background: Esophageal squamous cell carcinoma (ESCC) has high incidence and recurrence rates, particularly in advanced stages. While the combined positive score (CPS) and tumor proportional score (TPS) are standard benchmarks for PD-L1 assessment in ESCCs, they face challenges such as reliance on subjective human interpretation and the uncertain clinical significance of strong staining intensities. Our study utilizes H-scores for PD-L1 expression and separates analysis of tumor and stroma, providing additional layers of information that complement current methods and contribute to a more comprehensive understanding of the role of PD-L1 in ESCC.
Methods: This retrospective single-center cohort analysis involved 194 cases of ESCC who underwent surgical resection. We performed a comprehensive evaluation of PD-L1 expression within the tumor and stroma using whole slide images (WSI). QuPath image analysis software was used to classify regions as tumor or stroma and quantify the PD-L1 expression H-score.
Results: Using optimal H-score cutoffs determined from the minimum P-value method, the Kaplan-Meier survival analysis showed that higher PD-L1 expression was significantly linked with better post-operative survival across all compartments. This correlation was most pronounced in the stroma (P&lt;0.001). However, in multivariate Cox regression analysis, only high tumoral PD-L1 expression emerged as an independent predictor of favorable prognosis (HR=0.47, 95% CI: 0.27-0.81, P=0.007). The non-significant contribution of stromal PD-L1 in this model could be attributed to its association with advanced pT and pN stages, and the presence of lymphatic and venous invasion (P&lt;0.001, respectively). Interestingly, stromal PD-L1 expression was associated with a longer duration of cytotoxic chemotherapy (cutoff 8 months, Median H-score 98.28 vs 55.24, P=0.026), but no significant correlation was observed with the duration of immune checkpoint inhibitor treatment.
Conclusions: The study underscores the complex role of PD-L1 in ESCC, with tumoral PD-L1 expression emerging as an independent prognostic factor, and stromal PD-L1 expression found to be related with tumor progression and the duration of cytotoxic chemotherapy response.
Citation Format: Tomohiro Murakami, Satoru Furuhashi, Yuuki Sakai, Kenichi Sekimori, Ryoma Haneda, Eisuke Booka, Tomohiro Matsumoto, Hirotoshi Kikuchi, Yoshihiro Hiramatsu, Hiroya Takeuchi. Differential impacts of PD-L1 expression in tumor vs. stroma on survival in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 65.
Abstract 6518: BPM 31510: Targeting the tumor microenvironment (TME) via mitochondrial-mediated ROS production
Authors: Gesta Stephane , Nastke Maria D. , Nagpal Seema , Recht Lawrence , Kiebish Michael A. , Narain Niven R. , Modur Vijay R. 
Published: March 2024

Abstract
The tumor microenvironment (TME) consists of an enriched population of immune cells and milieu of factors that modulate key cellular processes such as angiogenesis, metabolism, apoptosis, migration, and proliferation. Previous studies have suggested that BPM 31510 induces ROS through high intra-cellular levels of ubidecarenone in aggressive cancer phenotypes both in vitro and in vivo through induction of mitochondrial ROS. Furthermore, we have previously observed efficacy of BPM 31510 in a highly aggressive in vivo orthotopic rat C6 glioma model where BPM 31510 was administered in combination with radiotherapy. In a pancreatic xenograft mouse model, we previously reported that BPM 31510 impacted the immune cells in the TME by increasing absolute number of infiltrated CD8+ T-cells and decreasing absolute number of infiltrated CD4+ T-cells. Moreover, an ex vivo study of PBMC’s from healthy volunteers suggests that BPM 31510 increases T-cell viability and function while also decreasing T-cell exhaustion. Currently, an ongoing first-line phase 2b study of BPM 31510 in glioblastoma in combination with radiotherapy and temozolomide will assess the clinical efficacy and potential for mechanistic synergy of multiple ROS-inducing mitochondrial mediated regimens on this aggressive cancer phenotype. BPM 31510 will be assessed in this study to provide further evidence for the impact of ROS on immunomodulation. Taken together, BPM 31510 increases mitochondrial ROS/OXPHOS in cancer cells while impacting TME-related immune cell modulation.
Citation Format: Stephane Gesta, Maria D. Nastke, Seema Nagpal, Lawrence Recht, Michael A. Kiebish, Niven R. Narain, Vijay R. Modur. BPM 31510: Targeting the tumor microenvironment (TME) via mitochondrial-mediated ROS production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6518.
Abstract 6523: TOX upregulation promotes a GPX4-dependent CD8+ T cell ferroptosis in tumor microenvironments
Authors: Li Jiang , Zhu Qian , Liu Xiufeng 
Published: March 2024

Abstract
Frequency and function of CD8+ tumor-infiltrating T cells (TILs) decide on clinical outcome of cancer immunotherapy; and TOX function as a crucial regulator of TIL dysfunction. In the present study, we found that multiplex factors, such as tumor cell, viral antigens and hypoxia, in tumor microenvironments (TME) induced CD8+ TIL ferroptosis by upregulating TOX. Single cell RNA-sequencing revealed that TOX modulated Havcr2, Pdcd1, Hmox1, Gpx4, and Ctsb transcription in human and murine CD8+ TILs. We further generated TOX conditional knockout in CD8+ T cell (Toxflox/floxCd8Cre, CKO) mice and the tumor-bearing CKO mice exhibited increased anti-tumor immunity and survival time. TOX upregulation increased reactive oxygen species (ROS), lipid peroxidation, and ferrous iron, leading to a GPX4-dependent CD8+ T cell ferroptosis. Genetic or antibody ablation of TOX, TIM-3, or HO-1 indicated that these molecules orchestrated CD8+ TIL ferroptosis by inducing iron overload and lipid peroxidation. Targeting TOX, PD-1, TIM-3, or ferroptosis boosted the anti-tumor suppression of tumor-specific T cell-based adoptive cell therapy (ACT) in murine tumor model. TOX, TIM-3 and GPX4 were prognostic predictors in human cervical cancer. This finding identifies a novel mechanism of tumor-induced CD8+ T cell ferroptosis underwent by TOX that provides new insights in improving TIL-based ACT immunotherapy.
Key words: TOX, CD8+ T cells, ferroptosis, tumor microenvironments, cancer immunotherapy
Citation Format: Jiang Li, Qian Zhu, Xiufeng Liu. TOX upregulation promotes a GPX4-dependent CD8+ T cell ferroptosis in tumor microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6523.
Abstract 6527: Fucosyltransferase 5 promotes immune evasion in ovarian cancer by suppressing double negative T cells
Authors: Fung S. W. , To Sally K. Y. , Hassan A. A. , Ip Phillip P.C. , Wong Alice S. T. 
Published: March 2024

Abstract
Emerging evidence suggests that aberrant glycosylation in cancer impact on various stages in the disease progression including immunomodulation, but the underlying mechanisms remain poorly understood. Our previous data demonstrated that fucosyltransferase 5 (FUT5), a glycosyltransferase responsible for the terminal step in synthesizing Lewis antigens, may contribute to peritoneal metastasis of ovarian cancer. In this study, using clinical samples of high grade serous ovarian cancer (HGSOC), the most common subtype, we found that high expression of FUT5 is associated with a worse outcome. By employing multiplex immunohistochemistry (IHC) to examine T cell subsets, we found a significant decrease in CD3+CD4−CD8− (double negative, DN) T cells in FUT5high (n=10) compared to FUT5low samples (n=10), while there is no difference in the abundance of CD8+ cytotoxic T cells, CD4+ helper T cells or CD4+Foxp3+ regulatory T cells. Tumor-infiltrating DN T cells has been shown to mediate potent anti-tumor response. In addition to their cytotoxic capabilities, DN T cells largely exhibit modulatory functions on other T cell subsets. To further investigate, we performed additional IHC staining and observed a significant increase in proliferating (Ki67+) CD8+ tissue resident memory cells, which are known to be important for cancer immunity. In addition, we observed a decrease in metastases in the FUT5 knockdown group, accompanied by an increase in DN T cells in ascites and omental metastatic tumors in humanised mice, as revealed by flow cytometry, confirming a direct immunomodulatory role of FUT5. Together, these findings reveal a novel role of FUT5 in promoting immune evasion by suppressing anti-tumor DN T cells, which could provide novel insights for immunotherapy in HGSOC, which has a low response rate to immune checkpoint inhibitors (This research is supported by RGC SRFS2223-7S05, HMRF 08192286 and LSCCB under the Health@InnoHK Program launched by ITC, HKSAR).
Citation Format: S. W. Fung, Sally K. Y. To, A. A. Hassan, Phillip P.C. Ip, Alice S. T. Wong. Fucosyltransferase 5 promotes immune evasion in ovarian cancer by suppressing double negative T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6527.
Abstract 6538: Modulation of human macrophage differentiation, phenotype and function in vitro as a strategy to characterize novel tumor microenvironment modulators
Authors: Castro Carla N. , Sahner Tamara , Obodozie Cynthia , Metzger Philipp , Weber Holger 
Published: March 2024

Abstract
Macrophage infiltration of the tumor microenvironment is a key process that can determine the success or failure of anti-tumor therapies. Thus, many immunooncology therapies are being developed to modulate the macrophage differentiation program towards the anti-tumor M1 subset, while hindering the M2 subset associated with tumor progression. Monocyte-derived macrophages comprise a crucial in vitro cellular tool to evaluate the plasticity potential between the different polarization states. Several hurdles like their in vitro adherence, low cell number yield and the donor-to-donor variability pose technical challenges when using in vitro differentiated macrophages for compound screening and titration or functional assays.
At Reaction Biology we have established human macrophage assay pipelines to evaluate the novel macrophage polarization compounds in vitro. By isolating monocytes from frozen PBMC stocks it is possible to have access to the same donor or group of donors PBMC for repetitive analysis. We have developed a differentiation protocol that allows us to use different plate format from 6-well to 48 well plates, and thus increase and modulate the throughput according to the required readout.
The effect of therapeutic compounds can be analyzed by flow cytometry. Our data shows that human primary monocytes grown under M1 polarizing conditions express high levels of CD86 and CD80 in contrast to those cultivated under M2 polarizing conditions, with high expression of CD163, CD206, and CD209. Cell culture supernatant can be used to determine cytokine secretion. The functionality of the different macrophage subtypes can be further investigated using a pH-sensitive phagocytosis tracker, like pHRodo-Zymosan or pHRodo-Ecoli, which shows differential uptake according to differentiation profile. Moreover, treated macrophages can be used in coculture with T cells to investigate their capability to foster or inhibit an immune response.
Our data shows the value of monocyte-derived macrophage assays in the evaluation and efficacy assessment of TME modulators.
Citation Format: Carla N. Castro, Tamara Sahner, Cynthia Obodozie, Philipp Metzger, Holger Weber. Modulation of human macrophage differentiation, phenotype and function in vitro as a strategy to characterize novel tumor microenvironment modulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6538.
Abstract 666: ASTX295 engages p53-mediated apoptosis and an inflammatory response in patient derived mesothelioma explants
Authors: Fennell Dean Anthony , Dzialo Joanna , Rogel Jan , Faulkner Daniel , Nusrat Nada , Bzura Aleksandra , Kutywayo Kudzayi , Wells-Jordan Peter , Poile Charlotte , Biondo Andrea , Sims Martin , Nakas Apostolos , Luo Jin-Li , Zhang Min , Ahn Maria 
Published: March 2024

Abstract
Mesothelioma is a universally lethal, rare cancer caused by asbestos that is lacking effective targeted treatments, particularly in the relapsed setting. P53 is predominantly wildtype (WT 83%) but is likely restrained by MDM2 particularly in the context of 9p21 deletion, a common, clonal somatic event affecting around half of all mesotheliomas that results in deletion of the MDM2 suppressor ARF. 9p21 deletion is also associated with a cold, immunosuppressed microenvironment. Unleashing p53WT by inhibiting its interaction with MDM2 has therapeutic potential in mesothelioma. To test this hypothesis, we employed live patient derived explants (PDEs) as a model that reflects the genomic inter-patient heterogeneity of mesotheliomas, and harbours an intact tumour microenvironment. Between August 2017 and April 2021 a total of 71 patients were consented prior to extended pleurectomy decortication, and PDEs were harvested at the time of surgery. PDEs were then cultured and treated with ASTX295, an inhibitor of p53-MDM2 interaction, using two concentrations (0.5 and 1 micromolar) and two timepoints (48 and 72 hours). PDEs passing quality control were subjected to spatial profiling using multiplex immunofluorescence microscopy. PDEs harbouring p53WT showed ASTX295-induced p21 (CDK1A) upregulation, which correlated with induction of apoptosis (p=0.04). PDE rank-order sensitivity was conserved across different doses and exposure-times. Transcriptome analysis confirmed ASTX295 induced p53 pathway activation in conjunction with a pro-inflammatory phenotype; both of which were absent in one PDE harbouring an inactivating p53 single nucleotide variant. Constitutive epithelial mesenchymal transition (EMT) was enriched in responding PDEs, as well as MDM2 inhibitor sensitive mesothelioma cell lines. 9p21 deletion (revealed by exome sequencing) was detected in both responding and non-responding PDEs. In summary, inhibition of MDM2-P53 interaction triggers robust p53 activation and a pro-inflammatory phenotype, which is potentiated in EMT enriched mesothelioma PDEs. ASTX295 is currently under clinical investigation (NCT03975387).
Citation Format: Dean Anthony Fennell, Joanna Dzialo, Jan Rogel, Daniel Faulkner, Nada Nusrat, Aleksandra Bzura, Kudzayi Kutywayo, Peter Wells-Jordan, Charlotte Poile, Andrea Biondo, Martin Sims, Apostolos Nakas, Jin-Li Luo, Min Zhang, Maria Ahn. ASTX295 engages p53-mediated apoptosis and an inflammatory response in patient derived mesothelioma explants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 666.
Abstract 6673: Tumor microbial burden is regulated by mast cells and determines immunotherapy responses
Authors: Rajaei Hajar , Jang Jeong-Hoon , Liu Haoyue , Faraoni Erika Y. , Le Roux Olivia , Chandra Vidhi , Tahan Virginia , Li Le , Riquelme Erick , White James Robert , Diaz Luis A. , McAllister Florencia 
Published: March 2024

Abstract
Immune checkpoint inhibitors (ICI) have notably improved overall survival rates across various cancers, particularly in cases of mismatch repair deficient cancer (MMRd). However, numerous factors influence patient response following ICI treatment. Beyond genetic factors, mutations, and levels of immune cell infiltration, several studies highlight the correlation between the gut microbiome and treatment response rates. Furthermore, specific bacterial compositions have been observed to shift during therapeutic interventions. Notably, studies have demonstrated that patients who used antibiotics before and during ICI treatment exhibited lower progression-free survival and overall survival, serving as evidence for this association. Our previous investigations elucidated the impact of distinct tumor microbial burdens on modulating immune activation. Consequently, our hypothesis posits the substantive involvement of the interplay between tumor microbial burden and the immune system response to ICI treatment.
We evaluated the presence of intra-tumoral microbes within Colorectal cancers (CRC) by examining TCGA data. Patients with elevated microbial levels demonstrated heightened immune activity and better survival rates. Using cybersport analysis, we validated increased mast cell infiltration in CRC patients with abundant microbes. Quantification involved assessing bacterial burden through 16s rRNA via FISH staining and mast cell counts using tryptase via IHC staining. Reducing bacterial load in MC38 cancer model, achieved by locally administering antibiotics, led to a diminished immune response when PD-1 was introduced to these mice. Cross-referencing TCGA data, we identified upregulated genes in CRC patients with high microbial burden and downregulated genes in mice receiving local antibiotics after MC38 cell implantation. The common genes were associated with immune responses, suggesting a strong correlation between bacterial burden and immune activity in CRCs. In conclusion, the high burden of bacteria in CRC improves immune response to ICI and increases the infiltration of mast cells, which all contribute to better survival rates.
Citation Format: Hajar Rajaei, Jeong-Hoon Jang, Haoyue Liu, Erika Y. Faraoni, Olivia Le Roux, Vidhi Chandra, Virginia Tahan, Le Li, Erick Riquelme, James Robert White, Luis A. Diaz Jr., Florencia McAllister. Tumor microbial burden is regulated by mast cells and determines immunotherapy responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6673.
Abstract 6756: Our RNA production platform and the associated tools facilitate the development of RNA-based vaccine
Authors: Bosso-Lefèvre Célia , Cirri Erica , Mennesson Eric , Szymczak Dimitri , Carpentier Flavien , Foucher Alexandra , Komarkova Alzbeta , Rochet Maxime , Vindrios Armelle , Goulay Romain 
Published: March 2024

Abstract
mRNA vaccines have shown their full potential in the Covid-19 pandemic. The application of these technologies for the treatment of cancers represents significant hope, but clinical effectiveness remains to be demonstrated. For this purpose, researchers require high quality production of vaccine mRNA and accurate and cost-saving test tools that are adapted to oncology research. Since 2021, Tebubio has developed a miniscale RNA production platform for providing RNAs (from 100 µg to 1 mg) to researchers around the world. This service is completed by offers on RNA delivery solutions using lipid nanoparticles (LNPs) and cellular tests with biomarker analysis. Through an ingenious design, our DNA matrix for mRNA is easily transferable for GMP production for clinical studies. Recently, Tebubio has developed DNA matrices for circular RNA production. Indeed, circular RNA has many advantages by being less immunogenic and more stable than linear RNA. We compared the quality and the quantity of CAP1 capped linear RNA and circular RNA produced from our DNA templates. We also assessed the stability of both RNAs expressing GFP and the typical tumor antigen, p53, and their relative expression into antigen-presenting cells (APCs). Finally, we quantified the response of the APCs expressing p53 by using our biomarker multiplex analysis system. This new type of RNA and its efficiency testing in APCs will constitute a new addition to our pipeline of RNA production and testing for preclinical studies.
Citation Format: Célia Bosso-Lefèvre, Erica Cirri, Eric Mennesson, Dimitri Szymczak, Flavien Carpentier, Alexandra Foucher, Alzbeta Komarkova, Maxime Rochet, Armelle Vindrios, Romain Goulay. Our RNA production platform and the associated tools facilitate the development of RNA-based vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6756.
Abstract 6812: Durable control of brain tumors by glioma inhibitory macrophages and IL33
Authors: Menon Shyam V. , Lun Xueqing , Zeng Peipei , Zhang Jianbo , Ahn Bo Young , Yu Henry , Poole Alisha , Dang Ngoc Ha , Osz Katalin , Chan Jennifer A. , Quail Daniela F. , Robbins Stephen M. , Senger Donna L. 
Published: March 2024

Abstract
Glioblastoma is the most common and deadly form of brain cancer. Even with aggressive treatment including surgery, chemotherapy, and radiotherapy, survival outcomes for newly diagnosed glioblastoma patients remains less than two years. Novel high throughput omics technologies have expanded our understanding of the role of innate immune system in brain tumors, that are generally believed to drive glioma progression and enable evasion of the adaptive immune system. However, targeting of this axis in the clinic remains an unmet opportunity. Previously, we discovered that the dual-function (secreted and nuclear) cytokine IL-33 is a crucial regulator of the inflammatory microenvironment that promotes glioma tumorigenesis through phenotypic and functional changes in the innate immune cell repertoire. Strikingly, when IL-33 is prevented from entering the nucleus, by deletion of its nuclear localization sequence (ΔNLS IL-33), but is still secreted, in vivo tumor growth is dramatically inhibited resulting in prolonged long-term survival. Using multiplex immunohistochemistry and spatial transcriptomics with temporal resolution across different stages of tumor progression, we identified a population of glioma-inhibitory macrophages (GIMs) unique to this suppressive environment. Assessment of GIMs in xenografts generated from patient brain tumor initiating cells found an enriched presence of these cells in xenografts with long-term survival (greater than 300 days) versus short-term survival (less than 100 days). The ability of GIMs to inhibit glioma progression was demonstrated when tumors established using a combination of ΔNLS IL-33 expressing cancer cells together with highly tumorigenic cells resulted in a growth inhibitory environment that significantly extended survival. A deeper molecular characterization of this phenotype and development of clinical strategies are currently underway.
Citation Format: Shyam V. Menon, Xueqing Lun, Peipei Zeng, Jianbo Zhang, Bo Young Ahn, Henry Yu, Alisha Poole, Ngoc Ha Dang, Katalin Osz, Jennifer A. Chan, Daniela F. Quail, Stephen M. Robbins, Donna L. Senger. Durable control of brain tumors by glioma inhibitory macrophages and IL33 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6812.