bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C172: PTX3 blockade restores anti-tumor immunity through suppressing M2-like macrophages phenotypes in colon cancer
Authors: Chen Feng-Wei 
Published: December 2023

Abstract
The tumor microenvironment is a chronic inflammatory condition which is composed of various types of stromal cells, immune cells, and cytokines. Cancer-associated fibroblasts and M2-like macrophages are involved in enhancing malignancy of colon cancer progression, such as tumor growth and immunosuppression. Identifying the cross-talk mechanisms among cancer cells, cancer-associated fibroblasts, and M2-like macrophages is important for development of cancer therapy. Pentraxin 3 (PTX3) is a secretory factor that is rapidly responsive to exposure of proinflammatory cytokines. The function of PTX3 is known to regulate innate immunity and tissue remodeling. However, its role in tumor progression appears to be context-dependent and unclear. In this study, we found that PTX3 is silenced in colon cancer cells due to epigenetic regulation but is primarily expressed by fibroblasts in colon tumors. Clinically, higher PTX3 expression is positively correlated with fibroblast and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Our results showed that PTX3 had no effect on cellular proliferation of fibroblasts or cancer cells in vitro, but blockade of PTX3 by specific monoclonal antibody significantly reduced stroma cell-mediated tumor growth in vivo. In addition, blockade of PTX3 reduced MC38 tumor growth in immunocompetent mice but had no effect in immunodeficient mice, suggesting the role of PTX3 in regulating tumor-immunity. Indeed, inhibition of PTX3 resulted in reduced numbers of M2-like macrophages and increased numbers of cytotoxic CD8 T cells in MC38 tumors. The expressions of cytotoxic markers in T cells were suppressed under exposure to conditioned media from PTX3-stimulated macrophages in vitro. We further revealed that PTX3 stimulated macrophage polarization toward an M2-like phenotype through activation of CREB/CEBPB axis. These findings suggest that PTX3 is involved in stroma cell-mediated protumoral immunity and targeting PTX3 by monoclonal antibody can be a potential therapeutic strategy in colon cancer treatment.
Citation Format: Feng-Wei Chen. PTX3 blockade restores anti-tumor immunity through suppressing M2-like macrophages phenotypes in colon cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C172.
Abstract C173: Negative selection of ligand-receptor interactions mediating lymphocyte infiltration confers melanoma resistance to Immune Checkpoint Blockade therapy by turning hot tumors to cold
Authors: Sahni Sahil , Wang Kun , Wang Binbin , Dhruba Saugato Rahman , Wu Di , Nagy Matthew , Ruppin Eytan 
Published: December 2023

Abstract
Immune checkpoint blockade (ICB) is a promising cancer therapy; however, response rates remain less than desired (less than ~40%) and resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (Immunotherapy Resistance cell-cell Interaction Scanner), a machine learning method aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to underlie ICB resistance in the tumor microenvironment (TME). Our approach considers two key components that such interactions should fulfill: they should be (1) differentially activated between the pre-treatment and post-treatment non-responderpatients, and (2) they should be predictive of ICB response in pre-treatment patients. We trained the model on the five largest publicly available melanoma bulk transcriptomics ICB cohorts and demonstrated its superior performance versus two states-of-the-art transcriptomics-based prediction methods (IMPRES and TIDE) in predicting ICB therapy response both in terms of RECIST criteria and patient survival. We further validated our identified resistance relevant LRIs in a melanoma single cell ICB cohort. Strikingly, LRIs highly activated in the pre-treatment group showed stronger predictive power for ICB response compared to the post-treatment non-responder group, which implies a potential negative selection of LRIs by tumors. Notably, many of these LRIs are mediating lymphocyte infiltration within the TME. Reassuringly, we further find a strong correlation between the activity of these LRIs and CD8+ T cells infiltration levels in the TME and are highly enriched in hot tumors in an independent cohort. Overall, these findings suggest that the tumor may develop resistance to ICB via inhibiting lymphocytes infiltration relevant ligand-receptor interactions, turning hot tumors to cold.
Citation Format: Sahil Sahni, Kun Wang, Binbin Wang, Saugato Rahman Dhruba, Di Wu, Matthew Nagy, Eytan Ruppin. Negative selection of ligand-receptor interactions mediating lymphocyte infiltration confers melanoma resistance to Immune Checkpoint Blockade therapy by turning hot tumors to cold [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C173.
Abstract C175: The potential effect of KRAS inhibitors on tumor microenvironments
Authors: Tanaka Noritaka , Sakamoto Takeharu 
Published: December 2023

Abstract
KRAS is one of the most common driver oncogenes among various cancer types. Researches aiming to develop KRAS inhibitors has been surging recently and the first clinical KRAS inhibitor sotorasib was approved for non-small cell lung cancer in the US and Japan. As KRAS activity has been reported to have certain effects on tumor microenvironments, KRAS inhibitor could potentially induce collateral outcomes on tumor microenvironment. Therefore, I have analyzed the potential influences of resistance to KRAS inhibitors on the tumor microenvironment. At first, I have established pancreatic cancer cell line MIA-Paca2 that acquired resistance to sotorasib, MIA/AMG-R, by continuously exposing them to sotorasib (1 µmol/L). An RNA sequencing analysis were performed with MIA/AMG-R and revealed that a gene set related to hypoxia were upregulated. When non-small cell lung cancer cell line NCI-H358 cells were exposed to sotorasib (1 µmol/L) for 4 hrs, the protein levels of HIF-1A decreased while that in MIA Paca-2 cells were unaffected. To evaluate at which steps of protein synthesis from gene transcription to through protein degradation of HIF-1A, NCI-H358 cells were treated with transcription inhibitor actinomycin D, translation inhibitor cycloheximide or proteasome inhibitor MG-132. The treatment of transcription inhibitor actinomycin D on NCI-H358 cells for 6 hrs did not lead to the decrease of HIF-1A protein level however, translation inhibitor cycloheximide induced drastic decrease in HIF-1A protein. Although exposure of NCI-H358 cells to MG-132 increased the expression level of HIF-1A, the combinational treatment of sotorasib and MG-132 still led to slight decrease in HIF-1A protein level. Also, MG-132 failed to recover the protein expression level decreased by cycloheximide treatment. In total, the cellular expression level of HIF-1A is possibly dependent on translation activity and KRAS inhibitor potentially affect the HIF-1A expression through the regulation of its translation. Conclusively, KRAS inhibitors could potentially be used to reprogram the hypoxic tumor microenvironments besides its primary effect against the downstream signaling of KRAS.
Citation Format: Noritaka Tanaka, Takeharu Sakamoto. The potential effect of KRAS inhibitors on tumor microenvironments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C175.
Abstract IA002: Inference of intercellular signaling activities in tumor spatial and single-cell transcriptomics, with applications in identifying cancer immunotherapy targets
Authors: Jiang Peng 
Published: December 2023

Abstract
My talk will present three computational frameworks we developed to study cytokine signaling activities and cell-cell communications during the antitumor immune response, using tumor single-cell and spatial transcriptomics. The basic immunology tool to study cytokine signaling mostly measures cytokine release, which is transient and does not represent downstream target activities. Therefore, we first developed the CytoSig platform, providing a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine, and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation, and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor. Then, based on CytoSig, we developed Tres, a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as TGF-β1, TRAIL, and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in multiple cancer types using bulk T cell transcriptomic data from pre-treatment patient tumors or infusion/pre-manufacture samples for cellular immunotherapies. Further, Tres identified FIBP as a candidate immunotherapy target to potentiate adoptive cell therapy efficacies. FIBP knockout in T cells enhanced adoptive cell therapy by down-regulating T cells' cholesterol metabolism. Last, I will briefly show our SpaCET framework for deconvolving cell fractions and identifying cell-cell interactions in tumor spatial transcriptomics data. SpaCET resolved several challenges in spatial transcriptomics analysis that previous methods did not address sufficiently. Through coupling cell fractions with ligand-receptor co-expression analysis, SpaCET reveals that intercellular interactions tend to be located at the tumor-immune boundaries.
Citation Format: Peng Jiang. Inference of intercellular signaling activities in tumor spatial and single-cell transcriptomics, with applications in identifying cancer immunotherapy targets [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA002.
Abstract IA004: Preclinical development of DuoBody®-CD3xB7H4, a novel CD3 bispecific antibody for the treatment of solid cancers
Authors: Koopman Louise A , Alemdehy Farshid , Paauwe Madelon , Vries Laura Smits-de , Karaiskaki Frosso , Brandhorst Marcel , Franken Patrick , Plantinga Theo S , Houtkamp Mischa A , de Poot Stefanie A.H. , Breij Esther C.W. 
Published: December 2023

Abstract
Several clinical trials are currently underway to investigate the effectiveness of CD3 bispecific antibodies (bsAb) in solid tumors. Given the number of approved CD3 bsAb therapies thus far, the development of these bsAbs appears to be more challenging in solid cancer compared to hematological malignancies. The choice of an appropriate tumor-specific target and CD3 affinity are important considerations for the development of effective and safe CD3 bsAbs. The immune checkpoint protein B7H4 is differentially expressed between normal and tumor tissue, showing high expression in various solid cancers. Therefore, B7H4 provides an attractive target for a CD3 bsAb. We explored the preclinical mechanism of action (MoA) and pharmacodynamic (PD) markers of two B7H4-targeting CD3 bsAbs with different CD3 affinities. By crosslinking CD3 on T cells with B7H4 on tumor cells, CD3xB7H4 bsAbs will induce T-cell mediated cytotoxicity in B7H4-expressing tumor cells, associated with T-cell activation and cytokine production. In comparative preclinical characterization studies in vitro, we showed that both bsAbs induced target-specific, dose-dependent, and complete tumor cell kill in a panel of tumor cell lines expressing varying levels of B7H4, albeit with different potency. Moreover, both molecules demonstrated an acceptable safety profile in cynomolgus monkeys. DuoBody-CD3xB7H4 (GEN1047), the variant with lower CD3 affinity, was selected as clinical candidate, to leverage its observed propensity for lower cytokine production. In a patient-derived xenograft model of ovarian cancer in NCG-HIS mice examined in vivo, DuoBody-CD3xB7H4 showed dose-dependent antitumor activity, which was associated with increased numbers of intratumoral T cells and with peripheral PD biomarkers of T-cell activation and cytokine production. Currently, DuoBody-CD3xB7H4 is being investigated in a first-in-human clinical trial for the treatment of solid tumors known to express B7H4 (NCT05180474), in which the MoA and PD, including biomarkers of response, will be clinically explored.
Citation Format: Louise A Koopman, Farshid Alemdehy, Madelon Paauwe, Laura Smits-de Vries, Frosso Karaiskaki, Marcel Brandhorst, Patrick Franken, Theo S Plantinga, Mischa A Houtkamp, Stefanie A.H. de Poot, Esther C.W. Breij. Preclinical development of DuoBody®-CD3xB7H4, a novel CD3 bispecific antibody for the treatment of solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA004.
Abstract IA009: Antibody-lectin chimeras for glyco-immune checkpoint blockade
Authors: Stark Jessica 
Published: December 2023

Abstract
Despite the curative potential of checkpoint blockade immunotherapy, a majority of patients remain unresponsive to existing treatments. Glyco-immune checkpoints – interactions of cell-surface glycans with lectin, or glycan binding, immunoreceptors – have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a tumor-targeting arm as well as a lectin “decoy receptor” domain that directly binds tumor glycans and blocks their ability to engage lectin receptors on immune cells. AbLecs enhanced cancer cell killing in vitro via macrophage phagocytosis and NK cell and granulocyte cytotoxicity compared to their parent monoclonal antibodies. AbLec treatment reduced tumor burden in vivo compared to treatment with the parent antibody in a humanized model of metastatic HER2+ cancer. Furthermore, AbLecs synergized with blockade of the “don’t eat me” signal CD47 for enhanced tumor killing. AbLecs can be readily designed to target numerous tumor-associated antigens and glyco-immune checkpoint ligands, and therefore represent a new modality of cancer immunotherapy.
Citation Format: Jessica Stark. Antibody-lectin chimeras for glyco-immune checkpoint blockade [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA009.
Abstract IA010: Engineering human sialidase as novel cancer therapeutics by targeting sialoglycans
Authors: Peng Li 
Published: December 2023

Abstract
Immune checkpoint blockade has revolutionized cancer treatment, but resistance remains a significant hurdle for many patients. Sialoglycans, as new immune checkpoints on tumors, present a promising therapeutic opportunity to enhance immune response. Cleaving off sialoglycans from tumors using a tumor-associated antigen (TAA) targeted antibody-bacterial sialidase conjugate has shown antitumor activity in preclinical models. Recognizing the immunogenicity risk of bacterial enzymes, we've engineered a human sialidase for therapeutic development. By investigating the roles of sialoglycans on immune cells, we've found that cleaving T cell surface sialoglycans boosts antitumor immunity. Additionally, we've demonstrated the efficacy and tolerability of the untargeted engineered human sialidase Fc fusion (Bi-Sialidase) as a potential immunotherapy. These advancements have led to the development of the EAGLE (enzyme antibody glycan editing) technology platform, which restores antitumor immunity by stripping sialic acids from immunosuppressive sialoglycans on both tumor and immune cells.
Citation Format: Li Peng. Engineering human sialidase as novel cancer therapeutics by targeting sialoglycans [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA010.
Abstract LB_A04: Quantitative digital spatial protein profiling of non-small cell lung cancer brain metastasis
Authors: Kim Tae Jung 
Published: December 2023

Abstract
Metastatic brain tumor is the most common form of adult central nervous system (CNS) tumor, and the majority of the cerebral metastasis originate from lung cancer. Along with recent combination strategies applying immune checkpoint inhibitor, evaluating tumor microenvironment of the brain metastasis (BM) needs to be unveiled. In this study, we tried to disclose immune context information of BM of non-small cell lung cancer (NSCLC) by using highly multiplex NanoString digital spatial profiling (DSP) method. Seven cases of NSCLC and metastatic brain tumor were evaluated. To detect proteins at quantitative and high multiplex with spatial resolution, NanoString optical barcoding technology was used to digitally profile protein expression in FFPE samples. Immuno-oncology protein targets, including immune cell markers and checkpoint proteins are included. DSP identified differentially expressed proteins between primary NSCLC and BM. Proteins associated with immune regulation, evasion, and adaptive immunity, such as IDO-1, PD1, PDL1, STAT3, PTEN, and CD44 revealed decreased expression in patients with BM (P&lt;0.01). The expression of pS6 was significantly increased in BM (P&lt;0.01), which is associated with activation induced T-cell death. This study demonstrated differentially expressed proteins in BM associated with immune regulation and evasion via NanoString DSP platform. This study highlighted the localized expression of immune-related proteins of BM in patients with NSCLC. Moreover, our results presented the possibility of using digitally quantified and spatially allocated novel method in BM eliminating the subjectivity and variability associated with the immunohistochemistry techniques.
Citation Format: Tae Jung Kim. Quantitative digital spatial protein profiling of non-small cell lung cancer brain metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A04.
Abstract LB_A21: NCI60 HTS384: The next phase of the NCI60 screen
Authors: Teicher Beverly A , Kunkel Mark W , Morris Joel , Taylor Ronald C , Dexheimer Thomas S , Coussens Nathan P , Doroshow James H 
Published: December 2023

Abstract
The NCI60 human tumor cell line screen, which has operated as a free service to the cancer research community for over 20 years, has proven to be an important drug discovery tool. The screen has operated using cutting-edge technology of the 1990s including a 96-well microplate format, a 2-day drug exposure period and following cell fixation, and a visible absorbance endpoint by the protein-staining dye sulforhodamine B (SRB). The SRB endpoint determines cell density based on protein content with a lower resolution limit of 1,000 – 2,000 cells. This report describes the next phase of this important cancer research tool, the NCI60 HTS384 screen format. While the cell lines remain the same, the screen is performed using 384-well microplates with a 3-day compound exposure period and a CellTiter-Glo luminescence endpoint. The CellTiter-Glo endpoint determines cell number based upon ATP content with a lower resolution limit of &lt;10 cells. To develop a baseline comparison, data were generated from a library of 1,000 FDA-approved and investigational small molecule anticancer agents by the two assay formats. Although the mean-graph patterns and COMPARE analyses are very similar for many compounds, there is a divergence between the two screens for some molecular targets. Within subsets of approved and investigational agents directed toward the same target (e.g., EGFR, BRAF/MEK/ERK, and PI3K inhibitors), the clustering of compound data from the NCI60 HTS384 screen is qualitatively similar to the clustering of compound data from the classic NCI60 SRB screen and there is a strong COMPARE correlation between the two screens. However, for some drug targets there is very little or no clustering between data from the two screens, although the clustering within each screen is moderate-to-good. Examples include mTOR rapalogs, BET bromodomain and NAMPRTase inhibitors. Differences in data between the two screens might be partially attributed to increases in the assay endpoint sensitivity and compound exposure time of the NCI60 HTS384 assay. Compounds submitted for NCI60 screening after September 30, 2023, will be tested in the modernized NCI60 HTS384 format. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I and by the Intramural Research Program of the NIH, National Cancer Institute.
Citation Format: Beverly A Teicher, Mark W Kunkel, Joel Morris, Ronald C Taylor, Thomas S Dexheimer, Nathan P Coussens, James H Doroshow. NCI60 HTS384: The next phase of the NCI60 screen [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A21.