bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB041: EZH2 and ATF6 sense metabolic stress to balance MHC class I antigen presentation in melanoma
Authors: Edmondson Jacob L. , Reed Megan R. , Morehead Lauren C. , Heflin Billie , Koss Brian , Tackett Alan J. 
Published: April 2023

Abstract
Unleashing the immune anti-tumor response through immune checkpoint inhibitors (ICIs) is a promising strategy to combat many solid-tumor malignancies, including metastatic melanoma. When successful, the anti-tumor response is potent; however, around half of melanoma patients fail to respond to ICIs. Patient responsiveness to ICIs has been characterized by increases in MHC class I (MHC-I) expression driven by increases in oxidative metabolism. Though the harsh conditions of the tumor microenvironment (TME) are known to be immunosuppressive, the specific mechanisms connecting metabolic stress and antigen presentation are not well understood. To recapitulate and investigate the ICI-responsive phenotype in vitro, a model of metabolic remodeling was developed which forces melanoma cells (A375, A101D, B16F10) to metabolically adapt to the absence of glucose. Proteomic profiling indicates a reversible, adaptive phenotype reminiscent of published ICI-responders, and pathway enrichment shows analogous increases in oxidative metabolism and restoration of MHC-I expression. This phenotype, and its impact on MHC-I expression, significantly increases tumor cell sensitivity to T-cell-mediated killing in vitro. Additionally, successful adaptive remodeling of JAK1 and IFNAR1 KO cell lines suggests the metabolism-mediated induction of MHC-I is independent of IFN signaling. Proteomic analysis of three metabolically conditioned melanoma cell lines identified downregulation of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) and the activating transcription factor ATF6 as key determinants of MHC expression. In these studies, we mechanistically explore the control of MHC-I antigen presentation through the transcriptional and post-translational dysregulation of ATF6 and EZH2. Here, we demonstrate that ATF6 overexpression, and thereby activation of the adaptive unfolded protein response (UPR), prevents induction of MHC by EZH2 inhibition. These data suggest EZH2 and ATF6 act to balance MHC-I antigen presentation during metabolic stress whereby loss of EZH2 increases and activation of ATF6 prevents MHC antigen presentation. Additional and ongoing studies coupling EZH2 and ATF6 inhibition will provide crucial insight into this mechanism and have the potential to influence adjuvant therapy development.
Citation Format: Jacob L. Edmondson, Megan R. Reed, Lauren C. Morehead, Billie Heflin, Brian Koss, Alan J. Tackett. EZH2 and ATF6 sense metabolic stress to balance MHC class I antigen presentation in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB041.
Abstract LB062: Identifying novel targets for CAR-T therapies from single cell RNA-sequencing data
Authors: Madan Sanna , Sinha Sanju , Schäffer Alejandro A. , Ruppin Eytan 
Published: April 2023

Abstract
Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized cancer treatment. While CAR-T has yielded tremendous clinical success for patients with liquid tumors, its potential remains to be unleashed against solid tumors. One key challenge is identifying optimal targets for these therapies: cell surface proteins that are expressed highly and uniformly by a tumor’s constituent malignant cells, and minimally so by healthy tissues. Employing a systematic, data-driven analysis, we first charted the landscape of existing CAR-T targets in the clinic, identifying the leading targets in each indication based on tumor selectivity and safety metrics. Next, from patient tumor single cell transcriptomics data, we performed a genome wide search across many different solid tumor types to identify new and candidate CAR-T targets with better selectivity and safety scores than extant ones. Remarkably, in almost all indications, we could not find such better targets, testifying to the near optimality of the current target space, at least in accordance with our measures. However, one striking exception is HPV-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR-T targets in clinics. Specifically, our investigation has discovered 20 novel CAR-T targets for treating HNSC and one for treating glioblastoma more precisely and safely.
Citation Format: Sanna Madan, Sanju Sinha, Alejandro A. Schäffer, Eytan Ruppin. Identifying novel targets for CAR-T therapies from single cell RNA-sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB062.
Abstract LB075: Cancers adapt to their mutational load by buffering protein misfolding stress
Authors: Tilk Susanne , Frydman Judith , Petrov Dmitri , Curtis Christina 
Published: April 2023

Abstract
In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.
Citation Format: Susanne Tilk, Judith Frydman, Dmitri Petrov, Christina Curtis. Cancers adapt to their mutational load by buffering protein misfolding stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB075.
Abstract LB081: Concurrent characterization of somatic nucleotide mutations, 5mC, and 5hmC methylation in clinical research samples using a single nanopore sequencing assay
Authors: Aganezov Sergey , Rescheneder Philipp , Beaulaurier John , James Phillip , Juul Sissel 
Published: April 2023

Abstract
Genomic and epigenomic variants accumulate during cancer progression, resulting in a tumor consisting of heterogeneous collections of cells, or clones, with distinct profiles of genomic and/or epigenomic alterations. The ability to characterize a broad set of somatic (epi)genomic variations simultaneously, using a single sequencing assay, facilitates cancer research and can help inform treatment.
Here we describe a comprehensive approach to analyze native tumor DNA with long nanopore reads. First, we demonstrate that shallow (&lt;1x) whole genome nanopore sequencing provides sufficient information to observe large-scale copy number aberrations. This enables rapid and affordable screening of samples with an aim of selecting those that contain variation(s) of potential interest; such samples can then be sequenced to higher coverages for a higher resolution picture of specific structural variants.
We further demonstrate an analysis workflow vimba for high coverage (&gt;30x) nanopore sequencing of tumor/normal datasets that detects clone- and haplotype-resolved structural variations in patient-derived research samples. We provide an example of haplotype- and breakpoint-resolved compounded amplification and loss of heterozygosity (LOH) of a region containing the EGFR gene in an admixed kidney tumor sample.
Finally, we describe the suitability of this assay to gather genome-wide (epi)genomic variations (e.g., SNPs, indels, SVs, microsatellite instability) across tumor samples of different cancer types. For the first time with native long nanopore reads we are able to capture 5mC and 5hmC methylation information and map it over some of the most challenging repetitive regions of the genome. This information can empower a better understanding of cancer-type-specific (epi)genomic alterations, which in turn can help map out the landscape for further research.
Our approach demonstrates how nanopore sequencing can be used as a single comprehensive platform to better understand and resolve the complexity of (epi)genomic somatic alterations in tumor samples.
Citation Format: Sergey Aganezov, Philipp Rescheneder, John Beaulaurier, Phillip James, Sissel Juul. Concurrent characterization of somatic nucleotide mutations, 5mC, and 5hmC methylation in clinical research samples using a single nanopore sequencing assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB081.
Abstract LB087: IFN-gamma targets tumor vascular endothelial cells, causing impaired perfusion and tumor growth suppression in adoptive T cell therapy
Authors: Lin Qiaoya , Olkowski Colleen , Choyke Peter L. , Sato Noriko 
Published: April 2023

Abstract
CD8 T cell-secreted interferon-gamma (IFNγ) is a key factor in controlling adoptive T cell therapy (ACT) outcome. However, IFNγ effects on non-tumor cells (e.g., stroma and blood vessels) that could indirectly impact the therapy are not well characterized. We aim to dissect the spatiotemporal effects of IFNγ in the tumor microenvironment in ACT and the underlying mechanism of the therapy. An ACT using ex vivo-activated ovalbumin (OVA)-specific OT-1 T cells suppressed the growth of MCA-205-OVA-GFP fibrosarcoma or MOC2-SIINFEKL oral squamous cell carcinoma in wild-type mice. However, in IFNγR1-deficient hosts, the ACT failed, indicating that non-tumor cells were crucial targets of IFNγ. Furthermore, the efficacy was also abrogated in bone-marrow chimeras generated by transferring the wild-type bone-marrow to lethally irradiated Tie2-Cre-Ifngr1flox/flox mice. As IFNgR1 expression is specifically deficient in endothelial cells in these chimeras, this result indicates that IFNγ action on endothelial cells is indispensable for ACT. Early after T cell transfer (1.5 days), the fraction of OT-1 T cells infiltrating the tumor was small (0.098% of CD45+ cells) but produced high IFNγ (36.3%), resulting in the peak IFNγ concentration (47.3 pg/ml) in the whole tumor tissue in a 7-day observation period. In contrast, the highest accumulation of OT-1 T cells with low IFNγ production (2.9%) was observed on Day 4.5. Intravital imaging revealed that at Day 1.5, IFN-γ-RES-YFP-OT-1 T cells with a high level of IFNγ secretion (strong YFP+ signal) localized mainly along the tumor vessels. While more OT-1 T cells were observed in the MCA-205-OVA-GFP tumor tissue near the blood vessels on Day 4.5 than on Day 1.5, their IFNγ secretion was minimal. Degeneration of endothelial cells was observed via electron microscopy 3-4.5 days after T cells transfer. Consistent with this finding, CD31+ endothelial cell density decreased on Day 4.5 compared to Day 1.5 and significantly reduced blood perfusion in the entire tumor as observed by near-infrared imaging after IR800-albumin infusion. H&E staining of tumor sections showed tumor necrosis on Day 4-7. In summary, our study demonstrates that endothelial cell targeting of CD8 T cell-derived IFNγ is critical for tumor suppression in ACT, impairing blood perfusion. These results provide novel insights into the mechanism of ACT.
Citation Format: Qiaoya Lin, Colleen Olkowski, Peter L. Choyke, Noriko Sato. IFN-gamma targets tumor vascular endothelial cells, causing impaired perfusion and tumor growth suppression in adoptive T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB087.
Abstract LB092: Identification of target antigens for logic-gated CAR-T therapeutics for the treatment of clear cell renal cell carcinoma: conditional targeting of CA9 with a PSMA PrimeR
Authors: Attanasio Nickolas , Gray-Rupp Levi , Zhou Stanley , Williams Samuel A. 
Published: April 2023

Abstract
Chimeric antigen receptor T (CAR T) cell therapeutics have produced curative outcomes in hematological malignancies but have yet to be developed into safe and effective therapies for solid tumors. A major obstacle to developing targeted therapies against solid malignancies is the identification of targets that are abundantly and broadly expressed on tumor cells while exhibiting an absence of expression on high toxicity risk normal tissues. Logic-gated CAR T cells that inducibly express CAR upon recognition of a target antigen by a secondary engineered priming receptor (PrimeR) offer a novel approach to permit conditional killing activity in the presence of two antigens. Here, we identify PSMA and CA9 as attractive priming and cytolytic antigen targets, respectively, in clear cell renal cell carcinoma (ccRCC). Using a bioinformatic discovery path, we show PSMA and CA9 mRNA are co-expressed in 94% of ccRCC tumors (n=530, TCGA). Immunohistochemical (IHC) assessments further reveal robust membranous PSMA and CA9 protein coexpression in 80% of ccRCC (n=416). Expression of CA9 and PSMA was evaluated across disease stage and co-expression was confirmed throughout disease progression. Distant metastases similarly showed evidence of common expression. In contrast, IHC assessment of normal tissues revealed limited membranous coexpression of PSMA and CA9 in normal high-risk toxicity tissues. These findings collectively support the utility of PSMA and CA9 as target antigens for AND-logic-gated therapeutics for the treatment of ccRCC.
Citation Format: Nickolas Attanasio, Levi Gray-Rupp, Stanley Zhou, Samuel A. Williams. Identification of target antigens for logic-gated CAR-T therapeutics for the treatment of clear cell renal cell carcinoma: conditional targeting of CA9 with a PSMA PrimeR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB092.
Abstract LB121: BrainChild-03: Intraventricular B7-H3 CAR T cells for recurrent/refractory central nervous system tumors and non-pontine diffuse midline glioma in children and young adults
Authors: Vitanza Nicholas A. , Gust Juliane , Ronsley Rebecca , Wilson Ashley L. , Huang Wenjun , Seidel Kristy , Albert Catherine M. , Pinto Navin , Orentas Rimas J. , Gardner Rebecca A. , Jensen Michael C. , Park Julie R. 
Published: April 2023

Abstract
Background: B7-H3 expression on central nervous system (CNS) tumors offers a potential therapeutic target for adoptive cellular therapy.
Methods: A 3+3 statistical design was employed to assess the safety of repeated B7-H3 chimeric antigen receptor (CAR) T cells administered into the intracranial ventricular system (ICV) using an intrapatient dose escalation without lymphodepleting chemotherapy in pts 1-26 years of age with recurrent/refractory CNS tumors including (non-pontine) diffuse midline glioma (DMG) (NCT04185038, Arm B). Primary endpoints were feasibility to manufacture sufficient CARs and safety of weekly infusions for 3 weeks of 4-week cycles for 2 cycles. Secondary endpoints were best overall response (BOR) and correlatives of CAR activity.
Results: CAR manufacturing was achieved in 20/22 (91%) enrolled pts. Eight pts were inevaluable (rapidly progressive exam precluding initial infusion (n=5), removal from protocol therapy due to progressive disease (n=2), and lack of evaluable disease prior to initial infusion (n=1)). No dose limiting toxicities were observed, identifying the maximally tolerated dose regimen (MTDR) as DR3 (maximum dose: 10 × 107 B7-H3CARs). Subjects received 98 ICV doses (median: 6 doses/patient, range: 3-13). For evaluable patients, the most common adverse events were headache (12/12, 100%), fatigue (9/12, 75%), nausea/vomiting (7/12, 58%), and fever (6/12, 50%). There was no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging analysis is ongoing with current BOR being stable disease. CAR T cells were detected in the CSF in 9/12 evaluable pts (75%). Serial CSF/serum cytokine analysis and mass spectrometry are in process.
Conclusion: Repeated ICV administration of B7-H3 CAR T cells is tolerable with circulating CAR T cells detectable in the CSF post infusion. Further investigation is warranted, along with future studies interrogating iterative enhancements such as modifications for enhanced potency and multi-antigen targeting.
Citation Format: Nicholas A. Vitanza, Juliane Gust, Rebecca Ronsley, Ashley L. Wilson, Wenjun Huang, Kristy Seidel, Catherine M. Albert, Navin Pinto, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. BrainChild-03: Intraventricular B7-H3 CAR T cells for recurrent/refractory central nervous system tumors and non-pontine diffuse midline glioma in children and young adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB121.
Abstract LB133: An orally bioavailable degrader targeting androgen receptor and the splice variant in castration resistant prostate cancer
Authors: Hung Chiu-Lien , Wang Ling-Yu , Fu Chih-Wei , Hsu Hung-Chih , Kung Hsin-Jien 
Published: April 2023

Abstract
The development and progression of prostate cancer depends on androgen receptor (AR) whose sustained activity albeit the use of anti-androgen drugs accounts for one of the major mechanisms leading to drug resistance. As such, the clinical benefits of current therapeutic agents remain rather limited for the advanced prostate cancer. Given that expression of constitutively active AR variants (AR-Vs) that lack the ligand-binding domain (LBD) clinically associates with the drug resistance and poor survival, targeting both AR and the LBD-truncated AR-Vs is anticipated an effective approach to overcome therapy resistance. Here, we present Proteolysis Targeting Chimeras (PROTAC) compound ITRI-148, capable of effectively degrading both full-length and LBD-truncated AR by targeting the proteins via the N-terminal domain to Cereblon-mediated ubiquitination and degradation. Degradation of AR and AR-V7 suppresses target gene expression, and inhibits cell proliferation with accompanied apoptosis activation in AR-V7-expressing castration-resistant prostate cancer (CRPC) cell models. In vivo, this compound displays good pharmacokinetics profiles and oral bioavailability with strong antitumor efficacy towards castration-, enzalutamide-resistant CWR22Rv1 and VCaP xenograft models. These data provide compelling evidence that by targeting AR NTD for induced degradation of active AR protein variants, ITRI-148 is a promising agent for the intervention of advanced therapy-resistant prostate cancers.
Citation Format: Chiu-Lien Hung, Ling-Yu Wang, Chih-Wei Fu, Hung-Chih Hsu, Hsin-Jien Kung. An orally bioavailable degrader targeting androgen receptor and the splice variant in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB133.
Abstract LB151: Exploring the tumor microenvironment in a spatial context with SpaCET
Authors: Ru Beibei , Huang Jinlin , Zhang Yu , Aldape Kenneth , Jiang Peng 
Published: April 2023

Abstract
Uncovering the composition and structure of the tumor microenvironment is critical to a mechanistic understanding of tumorigenesis and therapeutic resistance. Spatial transcriptomics (ST) technology has enabled profiling the molecular features of tumor tissue with position information. However, the spatial probe of various ST strategies with a 10~100 μm diameter might capture a mixture of transcripts from multiple cells or cell lineages. Cell type deconvolution in ST data of tumor tissues remains challenging for existing methods, which are designed to decompose general ST or bulk data. We develop the Spatial Cellular Estimator for Tumors (SpaCET) to infer cell identities from tumor ST data. Without the need of inputting cell references, SpaCET estimates malignant and non-malignant cell abundance by using a gene pattern dictionary of copy number alterations in common malignancies and a hierarchical atlas of immune/stromal cells, respectively. SpaCET provides higher accuracy than existing methods based on eight ST datasets on seven cancer types with matched double-blind histopathology annotations as ground truth. Furthermore, SpaCET can reveal the potential intercellular interactions at the tumor-immune interface by integrating inferred cell fractions with the ligand-receptor interaction network. We expect that SpaCET will be a valuable tool for spatial cancer biology.
Citation Format: Beibei Ru, Jinlin Huang, Yu Zhang, Kenneth Aldape, Peng Jiang. Exploring the tumor microenvironment in a spatial context with SpaCET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB151.