bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3609: Chimeric cytokine receptors increase memory phenotypes and improve expansion and efficacy of CAR-T cell therapies
Authors: Newcomb John R. , Ren Jun , Syed Sakeena , Caruolo Zachary , Webb Lindsay , McKay Craig , Kwei Stephanie , Novina Carl , Mermelstein Fred 
Published: March 2024

Abstract
Cytokine activation of T cells can promote T cell proliferation, memory and improve T cell function in driving tumor cell killing. However, systemic administration of cytokines at therapeutic doses is also associated with unacceptable toxicities. To overcome this limitation, we have engineered a system of private cytokine signaling to affect T cell homeostasis, identity, and function. Specifically, we have engineered chimeric cytokine receptors (CCRs) composed of single-chain variable fragments (scFvs) that bind specifically to small molecules such as fluorescein or DOTA. These scFvs are fused to transmembrane and intracellular domains of all members of the common gamma-chain (γ-chain) family of cytokine receptors. CCRs that permit private cytokine signaling were introduced into known CAR-T cell therapies and their impact on CAR-T cell phenotype, function, and anti-tumor activity was tested. First, CCR-containing T cells were tested for activation-induced changes in phenotype and expansion following stimulation with small molecule conjugates in vitro. The most promising results were obtained using either the IL-7Rα- or IL-2Rβ/γ-containing CCR’s. CCR-containing constructs were then transduced into one of two different anti-BCMA CAR-T constructs, ide-cel or cilta-cel, using a lentiviral transduction system. CAR-T cells containing each CCR were then compared with CAR-T cells lacking CCRs for phenotype and function in vitro. Results indicated that engineering the IL-7Rα CCR with both of these CAR-T’s led to increased expansion, cytokine secretion and improved tumor cell killing. Next, CAR-T cells expressing the IL-7Rα CCR were compared to CAR-T cells lacking CCR for efficacy and durability in a mouse model of human multiple myeloma. IL-7Rα CCR-expressing CAR-T cells demonstrated improved long-term tumor control compared to ide-cel and cilta-cel alone. In addition, IL-7Rα CCR-expression increased T cell numbers in blood, spleen and bone marrow of tumor-bearing mice. These increases were particularly evident in the CD8+population of CAR-T cells in vivo. These results demostrate that private cytokine signaling using small-molecule activatable CCRs can improve efficacy and durability of CAR-T cells. We are testing these CCRs in mouse models of human solid tumors to assess their ability to overcome the immunosuppressive microenvironment.
Citation Format: John R. Newcomb, Jun Ren, Sakeena Syed, Zachary Caruolo, Lindsay Webb, Craig McKay, Stephanie Kwei, Carl Novina, Fred Mermelstein. Chimeric cytokine receptors increase memory phenotypes and improve expansion and efficacy of CAR-T cell therapies [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 3609.
Abstract 3645: Unraveling spatial complexity of the tumor microenvironment: A whole transcriptomic perspective with Visium HD
Authors: Yin Yifeng , Sapida Jerald , Sukovich David , Patterson David , Tentori Augusto 
Published: March 2024

Abstract
In recent years, advances in spatial transcriptomics have revolutionized our understanding of the tumor microenvironment, providing crucial insights into the complex interplay of different cell types within cancer tissues. In this study, we employed the new, high definition Visium spatial transcriptomics assay (Visium HD) to investigate the intricate molecular landscape of prostate cancer at single-cell scale resolution and across the whole transcriptome. Our research focused on deciphering the spatial heterogeneity of gene expression patterns within the tumor microenvironment, shedding light on the interactions between cancer cells, stromal cells, and vasculature.
The Visium HD assay enables an unbiased exploration of the transcriptome on FFPE tissue sections mounted on standard glass slides. Combining gene expression data with H&E images from the same section, it allows precise characterization of local molecular features and disease states at single-cell scale. We analyzed a set of human prostate adenocarcinoma samples with the Visium HD assay, and identified spatially regulated gene signatures associated with specific cell types and functional pathways. Our findings have recapitulated previously identified molecular markers, including VEGFA and MYC which have been implicated in tumor progression and angiogenesis. The spatial gene expression patterns had good correlation with histological annotations of cancerous and normal tissue within the H&E image. However, Visium HD allowed us to further observe molecular processes and pathways specific to this adenocarcinoma sample. This integrative approach offers valuable implications for personalized cancer therapy and the development of targeted interventions tailored to the spatial context of individual tumors.
Our study underscores the significance of understanding the spatial organization of the whole transcriptome in cancer tissues, and highlights the potential of the Visium HD platform as a powerful tool for unraveling the complexities of the tumor microenvironment. These insights pave the way for the development of innovative therapeutic strategies and precision medicine approaches, ultimately contributing to improved outcomes for cancer patients.
Citation Format: Yifeng Yin, Jerald Sapida, David Sukovich, David Patterson, Augusto Tentori. Unraveling spatial complexity of the tumor microenvironment: A whole transcriptomic perspective with Visium HD [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 3645.
Abstract 3719: Fasting-mimicking diet plus 2-DG drives antitumor immunity by targeting EDEM3-induced PD-L1 glycosylation
Authors: Liu Xiaoxia , Peng Shaoyong , Wang Xiaolin , Yu Huichuan , Luo Yanxin 
Published: March 2024

Abstract
The PD-1/PD-L1 axis plays an essential role in immune escape and immunotherapy. Importantly, translated N-linked glycosylation of PD-L1 stabilizes protein, enters the cell membrane binding to PD-1, renders T cells anergic and leads to T-cell exhaustion and dysfunction. Targeting PD-L1 glycosylation as an attractive target by a rational combination of cancer immunotherapies. Cancer-associated fibroblasts (CAFs), a predominant cell component of the tumor microenvironment, exert crucial functions in promoting immune escape and immunotherapy resistance by increasing the tumor PD-L1 expression. However, whether and how CAFs upregulate the glycosylation of PD-L1 has never been reported. This study shows that CAFs can upregulate PD-L1 glycosylation and enhance PD-L1 cell surface expression via glycosyltransferase EDEM3, thus cancer immune evasion. Then, the study delves into the relationship between EDEM3 expression, prognosis and immunogenicity. We demonstrate that EDEM3 plays a role in tumor immunity during tumor progression, as evidenced by EDEM3 expression is only significantly correlated with poor prognosis in the CD8+ T cell-enriched population. In subcutaneous tumor models, we observed high cell-surface PD-L1 expression accompanied by decreased CD8+ T cell infiltration and increased M2 macrophage in immunocompetent mice transplanted with EDEM3 over-expressed CRC cells that promote resistance to PD-1/PD-L1 blockade cancer immunotherapy. By performing bioinformatic analysis, we found that the hexosamine biosynthesis pathway (HBP) is highly affected in EDEM3-upregulated CRC cancer. Subsequently, the production of the UDP-GlcNAc (the end product of HBP metabolic flow), a donor substrate for N-linked glycosylation, is significantly increased in EDEM3 over-expressed CRC cells by LC/MS. Meanwhile, glucose is confirmed to be the primary effector of PD-L1 glycosylation in CRC cells, and the glucose restriction attenuates EDEM3-modified PD-L1 glycosylation by reducing UDP-GlcNAc biosynthesis. Finally, we demonstrate that modulation of glucose metabolism through a fasting-mimicking diet (FMD) in combination with 2-deoxy glucose (2-DG) treatment enhances antitumor immunity, especially in tumors with high-EDEM3 expression that exhibit resistance to immunotherapy. We propose potential therapeutic targets for CRC that inhibit PD-L1 glycosylation through FMD+2-DG and could augment the efficacy of immune checkpoint blockers.
Citation Format: Xiaoxia Liu, Shaoyong Peng, Xiaolin Wang, Huichuan Yu, Yanxin Luo. Fasting-mimicking diet plus 2-DG drives antitumor immunity by targeting EDEM3-induced PD-L1 glycosylation [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 3719.
Abstract 3731: Spliceosome: A gatekeeper for necroptosis
Authors: Jiang Xinpei , Ma Xueying , Balachandran Siddharth , Cañadas Israel 
Published: March 2024

Abstract
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with a 5-year overall survival of approximately 5%. SCLC has high prevalence of somatic mutations, yet express low to zero neoantigen. Despite promising advances in immunotherapy, highly metastatic SCLC remains a devastating disease and only a small fraction of SCLC patients respond to immunotherapy. These poor survival and lack of therapy options stresses the unmet need to identify novel and effective targeted therapies for metastatic SCLC. Here, we demonstrate that targeting the splicing core component, SF3B1, in SCLC, is a molecular trigger for tumor killing and viral mimicry.SF3B1 inhibition through the small molecule Pladienolide B (PlaB) induces the accumulation of immunogenic double-stranded RNAs (dsRNAs), including right-handed dsRNA conformation (A-RNA), provoking a tumor-intrinsic innate immune response and tumor cell death in SCLC preclinical models. Strikingly, we discovered that PlaB treatment also induces the formation of Z-form nucleic acids (Z-NAs), which are unique, left-handed nucleic acids and necroptosis-activating ligands for the host sensor ZBP1.These endogenous A-RNAs and Z-NAs initiate tumor-intrinsic antiviral interferon (IFN) signaling in SCLC cells leading to tumor-intrinsic immunogenicity and apoptosis. Notably, we also found that Z-NAs derived from spliceosome inhibition trigger the activation of ZBP1, inducing RIPK3-mediated MLKL activation and eventual necroptosis, a highly immunogenic cell-death pathway, in ‘necroptosis competent’ cells, including mouse embryonic fibroblasts (MEFs). This opens unexplored strategies for spliceosome inhibitors to activate anti-tumor immune pathways not only in tumor cells themselves, but also in cells of the Tumor Microenvironment (TME), which too can break tolerance and enhance anti-tumor T cell responses which is crucial to enhance cancer immunotherapy responses. These findings demonstrate a unique and novel spliceosome-targeted mechanism to remodel the immunosuppressive TME of SCLCs. Also, our study suggests that SF3B1 inhibitors and potentially other spliceosome inhibitors might be used not only to selectively kill tumor cells, but also as compounds to generate Z-NAs in tumor cells and cells of the TME and trigger on-demand necroptosis without need for an active virus infection.
Citation Format: Xinpei Jiang, Xueying Ma, Siddharth Balachandran, Israel Cañadas. Spliceosome: A gatekeeper for necroptosis [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 3731.
Abstract 3788: EpCAM+ DCCs isolated from the bone marrow of breast cancer patients display high stemness and potency scores
Authors: Raya Elia , Koerkel-Qu Huiqin , Rudhart Laura , Köhler Lisa-Marie , Damboeck Anna , Irlbeck Christoph , Botteron Catherine , Werner-Klein Melanie , Seitz Stephan , Klein Christoph 
Published: March 2024

Abstract
Metastatic dissemination of cancer cells from primary to distant sites often occurs early and it has been shown that their detection is linked to poor outcomes. Eradication of disseminated cancer cells (DCC) has therefore become the primary goal of adjuvant therapies. Since the phenotype of DCC is largely unknown, we set out to search, isolate, and molecularly characterize these candidate metastasis founder cells from bone marrow of breast cancer patients, years before manifestation of metastasis.
We screened more than 200 bone marrow samples of breast cancer patients with no evident metastasis (UICC stage M0) for EpCAM-positive cells. EpCAM positive cells in the bone marrow of healthy donors were used as a negative control. In addition, we isolated DCC from breast cancer patients with manifest metastasis (UICC stage M1). We then performed single cell RNA sequencing after whole transcriptome amplification of the collected DCC and the healthy donor (HD) control cells. To confirm the malignant origin of picked DCCs, we projected the transcriptome data into the bone marrow atlas, inferred copy number alterations, and searched for mutations shared with the matched primary tumor. EpCAM-positive cells from control patients mostly comprised plasma cells. In contrast, DCCs derived from M0-stage breast cancer patient formed a unique, non-overlapping cluster in the bone marrow atlas. UMAP-clustering placed M1-stage DCC clearly separate from M0 stage DCC. Among the collected M0-stage DCCs, we identified at least three separate subclusters. Strikingly, M0-stage DCC displayed much higher stemness and potency scores than M1-stage DCCs, reminiscent of embryonic cells. DCCs, identified by EpCAM, display very high transcriptional stemness scores when isolated before metastatic manifestation. Upon expansion and proliferation, stemness scores are reduced indicating epithelial re-differentiation. The embryonic phenotype of M0-stage DCCs may reflect an early adaptive mechanism that enables DCC to survive in an ectopic environment and may impact on the metastatic potential of the DCC.
Citation Format: Elia Raya, Huiqin Koerkel-Qu, Laura Rudhart, Lisa-Marie Köhler, Anna Damboeck, Christoph Irlbeck, Catherine Botteron, Melanie Werner-Klein, Stephan Seitz, Christoph Klein. EpCAM+ DCCs isolated from the bone marrow of breast cancer patients display high stemness and potency scores [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 3788.
Abstract 3801: Spatially resolved laser-activated cell sorting (SLACS) for high throughput spatial cell sorting in tumor research
Authors: Lee Sumin , Lee Amos Chungwon 
Published: March 2024

Abstract
Understanding of tumor heterogeneity and the microenvironment is a cornerstone in advancing cancer research and therapy. The Spatially resolved Laser-Activated Cell Sorter (SLACS) represents a novel approach in cancer research, allowing for high-throughput, precise cell isolation while preserving spatial information, which is crucial for studying tumor heterogeneity and the tumor microenvironment. The SLACS instrument utilizes laser-activated technology for selective isolation of cells from heterogeneous tissue samples, optimized for accuracy, speed, and minimal cell damage. This instrument has demonstrated effective isolation of specific cell types from complex tissue matrices, maintaining cell integrity and spatial information. Its high-throughput capacity significantly reduces sample processing time. This groundbreaking tool offers detailed exploration of tumor heterogeneity and the tumor microenvironment, providing valuable insights into cancer biology and potential therapeutic targets.
Citation Format: Sumin Lee, Amos Chungwon Lee. Spatially resolved laser-activated cell sorting (SLACS) for high throughput spatial cell sorting in tumor research [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 3801.
Abstract 3881: Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression
Authors: Zhou Haibin , Wu Dimin , Bai Longchuan , Acharyya Ranjan K. , Metwally Hoda , McEachern Donna , Wen Bo , Sun Duxin , Wang Shaomeng 
Published: March 2024

Abstract
STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic targets for cancer and other human diseases. We have previously reported the discovery of SD-36 and SD-91 as potent, selective and highly efficacious STAT3 degraders. In the present study, we report the discovery and extensive evaluation of new, highly potent, selective and efficacious new STAT3 degraders. In direct comparison, these compounds are &gt;50-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates &gt;500-fold degradation selectivity over other STAT members. Proteomic analysis showed that our best lead compound (UM-STAT3-1218) only reduces the levels of STAT3 protein in cells over other &gt;6,700 proteins. (UM-STAT3-1218) achieves low nanomolar IC50 values in leukemia and lymphoma cancer cell lines with activated STAT3. A single intravenous dose of (UM-STAT3-1218) at 3 mg/kg reduces the STAT3 protein for &gt;4 days in xenograft tumor and native tissues, without reducing another other STAT members. Impressively, a single dose of (UM-STAT3-1218) at 3 mg/kg achieves complete and long-lasting tumor regression in multiple xenograft tumor models without any signs of toxicity. Taken together, (UM-STAT3-1218) is a highly promising STAT3 degrader for the treatment of the treatment of human cancers and other human diseases in which STAT3 plays a key role.
Citation Format: Haibin Zhou, Dimin Wu, Longchuan Bai, Ranjan K. Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression [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 3881.
Abstract 3906: Ex vivo breast tumors for understanding the patient specific tumor microenvironment remodeling and drug responses
Authors: Martin Elizabeth , Benz Megan , Hebert Katie , Byrne Ethan , Lau Frank 
Published: March 2024

Abstract
Breast cancer is a heterogeneous disease driven by cell-intrinsic and cell-extrinsic signaling cues. Many of these cues derive from the tumor microenvironment (TME), which is composed of adipocytes, vasculature, stem cells, immune cells, and the extracellular matrix (ECM). Through these diverse components, the TME modulates cellular proliferation, survival, and ultimately response to therapy. Despite this high-level understanding of tumor-TME crosstalk, no existing pre-clinical models accurately capture the TME in vitro. We overcame that hurdle by developing a method to maintain healthy human breast tissue (HBT) alive ex vivo for at least 8 weeks. By culturing breast cancer cells in that HBT, we created ex vivo breast tumors (EVBTs) that retained patient-specific features relevant to breast cancer including menopause status, obesity status, and response to therapy. Using these EVBTs, we demonstrate breast cancer subtype-specific alterations in lipid accumulation, ECM remodeling, and cytokine profiles. RNA sequencing showed that breast cancer cell line signatures were retained in the EVBTs system at 1 week and 2 weeks in vitro. We demonstrated donor-specific transcriptional changes to the core matrisome gene set. Finally, we demonstrate that our EVBTs retained patient-specific heterogeneity in response to standard of care endocrine therapy and neoadjuvant chemotherapies. Our novel tumor model allows for 1) real-time examination of breast cancer interactions with HBT and the TME and 2) the isolation of breast cancer-specific factors vs. patient-specific factors in the development and progression of breast cancer.
Citation Format: Elizabeth Martin, Megan Benz, Katie Hebert, Ethan Byrne, Frank Lau. Ex vivo breast tumors for understanding the patient specific tumor microenvironment remodeling and drug 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 3906.
Abstract 3973: Cancer B cell blueprint reveals dysfunctional extra-follicular dominance with therapeutic opportunity
Authors: Ma Jiaqiang , Wu Yingcheng , Ma Lifeng , Yang Xupeng , Zhang Tiancheng , Guo Guoji , Fan Jia , Zhang Xiaoming , Gao Qiang 
Published: March 2024

Abstract
B cells are essential components of humoral immunity but harbor multifaceted functions across cancers. To decode tumor-infiltrating B cells, we generated the B cell blueprint encompassing single-cell transcriptome, BCR repertoire, and chromatin accessibility data across 20 cancer types (483 samples, 266 patients). Strikingly, B cells harbored extraordinary heterogeneity and composed of 15 subsets, which were grouped into two independent developmental paths (extra-follicular [EF] versus germinal-center [GC]) exhibiting organ preference. Of note, colon adenocarcinoma and hepatocellular carcinoma are the two representative types of cancer enriched for GC and EF pathways, respectively. We affirm that EF-dominant cancers correlate with dysregulated immune responses and worse clinical outcomes. We then identify the dynamic metabolic-epigenetic-signaling networks in fine-tuning tumor-infiltrating B cell differentiation and managing the balance between the EF and GC pathways. Atypical memory (AtM) B cells, the primary progenitors of EF-derived ASCs, exhibit an exhausted and bystander phenotype and develop independently of the GC pathway. We find that the AtM B cells reside in the center of immature TLSs and spatially relocate to the periphery during TLS maturation. Finally, we mechanistically link these findings to specific transcription factors and epigenomic regulations. We demonstrate that the glutamine-derived metabolite α-ketoglutarate (αKG) could increase the expression of AtM B cell associated transcription factors Tbet and BATF and promote their differentiation, accompanied by the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Consequently, AtM B cells acquire an immunoregulatory function that dampens anti-tumor T cell responses and fosters an immunosuppressive microenvironment.
Citation Format: Jiaqiang Ma, Yingcheng Wu, Lifeng Ma, Xupeng Yang, Tiancheng Zhang, Guoji Guo, Jia Fan, Xiaoming Zhang, Qiang Gao. Cancer B cell blueprint reveals dysfunctional extra-follicular dominance with therapeutic opportunity [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 3973.