bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A019: Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells infiltrating human tumor
Authors: Punyawatthananukool Siwakorn , Matsuura Ryuma , Wongchang Thamrong , Katsurada Nao , Tsuruyama Tatsuaki , Tajima Masaki , Enomoto Yutaka , Kitamura Toshio , Kawashima Masahiro , Toi Masakazu , Yamanoi Koji , Hamanishi Jyunzo , Hisamori Shigeo , Obama Kazutaka , Charoensawan Varodom , Thumkeo Dean , Narumiya Shuh 
Published: October 2024

Abstract
PGE2 is a predominant lipid mediator in the tumor microenvironment, synthesized by the action of the cyclooxygenase (COX). In mice, inhibiting PGE2 signaling suppresses tumor progression. In humans, daily use of COX inhibitors, such as aspirin and NSAIDs, reduces cancer initiation and mortality. While numerous immunosuppressive mechanisms of PGE2 have been suggested, most are based on animal models, leaving PGE2-mediated immunosuppressive mechanisms in human cancer largely unknown. In this study, we used comparative single-cell RNA-sequencing of human and syngeneic mouse tumors to dissect the function of PGE2 . We found in CD8+ T cells that high expression of PGE receptor EP4 and to a lesser extent EP2, is associated with downregulation of IL-2-STAT5 signaling, oxidative phosphorylation (OXPHOS), glycolysis, as well as MYC target genes such as ribosomal proteins (RPs). A similar downregulation of OXPHOS, glycolysis, and RP gene expression was also found in infiltrating myeloid cells. Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation. In activated CD8+ T cells, PGE2-EP2/EP4 signaling blocks IL-2-STAT5 signaling by downregulation of Il2ra, which in turn downregulates c-Myc and PGC-1, leading to decreased OXPHOS, glycolysis, and ribosome biogenesis. This results in reduced migration activity, poor survival and expansion capacity, and consequently impaired anti-tumor immunity. Similarly, EP4 and EP2 are induced upon activation in macrophages, and PGE2 downregulates Myc pathway and OXPHOS in these cells in M0 and M1 states. These results suggest that PGE2 impairs both adaptive and innate immunity in the tumor microenvironment by hampering their bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells via EP4 and EP2 receptors.
Citation Format: Siwakorn Punyawatthananukool, Ryuma Matsuura, Thamrong Wongchang, Nao Katsurada, Tatsuaki Tsuruyama, Masaki Tajima, Yutaka Enomoto, Toshio Kitamura, Masahiro Kawashima, Masakazu Toi, Koji Yamanoi, Jyunzo Hamanishi, Shigeo Hisamori, Kazutaka Obama, Varodom Charoensawan, Dean Thumkeo, Shuh Narumiya. Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells infiltrating human tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A019.
Abstract A028: Cycling T regulatory cells architect an immune escape hub during in situ to invasive breast carcinoma transition
Authors: Bui Triet Minh , Rojas Ernesto A , Foidart Pierre , Li Zheqi Vaciry , Yan Pengze , Nishida Jun , West Robert , Hwang Shelley , Cristea Simona , Polyak Kornelia 
Published: October 2024

Abstract
The tumor immune microenvironment shapes breast tumor evolution. We previously described the ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) transition as an evolutionary bottleneck and a key step of immune escape. Here, we dissected the cellular composition and spatial topology of DCIS and IBC patient samples and rat tumors that faithfully recapitulate human breast cancer. We identified differences in T cells as the main distinguishing feature between DCIS and IBC and discovered a novel cycling regulatory T cell population (cycTreg) as the primary orchestrator of the immune suppressive environment during invasive progression, especially enriched in triple-negative histological subtype. We showed that cycTregs are locally expanding Treg precursors in response to increased antigen presentation, and further demonstrated that modulating them by OX40 agonist in combination with anti-PD-L1 enhances CD8+ T cell infiltration and suppresses tumor growth. Characterizing therapeutic responses at the single cell level revealed a Treg and cancer-associated fibroblast (CAF) crosstalk via IL33-ST2 pathway that is critical for Treg expansion. Multimodal analysis of the patient cohorts demonstrated that cycTregs predict recurrence in low-grade DCIS and poor patient outcomes in IBC, and that increased CAF-immune-DCIS proximity is prognostic of progression to IBC. In sum, our study establishes cycTregs as key drivers of immune escape during invasive progression and implies that their targeting is essential for enhancing the efficacy of immune checkpoint inhibitors in IBC.
Citation Format: Triet Minh Bui, Ernesto A Rojas, Pierre Foidart, Zheqi Vaciry Li, Pengze Yan, Jun Nishida, Robert West, Shelley Hwang, Simona Cristea, Kornelia Polyak. Cycling T regulatory cells architect an immune escape hub during in situ to invasive breast carcinoma transition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A028.
Abstract A047: Activation of conventional type 2 dendritic cells (cDC2) by anti-CD47 may enhance antitumor T cell function in mouse liver cancer models
Authors: Jian Cheng-Zhe , Ou Da-Liang , Hsu Chia-Lang , Lee Chien-Kuo , Hsu Chiun 
Published: October 2024

Abstract
Anti-CD47 has been extensively studied for its effects on activating phagocytosis by blocking the ‘don’t eat me’ signal presented by CD47 expressed on cancer cells. This study explored the effects of anti-CD47 on enhancing antigen presentation by dendritic cells and improving antigen-specific antitumor immunity. Mouse Hepa1-6 liver cancer cells with or without over-expression of LCMV-GP protein and splenocytes from P14 transgenic mice were used to test antigen-specific antitumor immunity. Bone marrow-derived conventional type 1 and type 2 dendritic cells (cDC1 and cDC2) or MutuDC1/ DC2 cell lines were co-cultured with CD8 T cells with or without exhaustion. Effects of anti-CD47 on the cross-priming ability of DC were analyzed by T cell proliferation (CSFE labeling), activation (expression of IFNγ, granzyme B, TNFa, and IL-2), cell killing (in vitro cytotoxicity assay) and T cell exhaustion (LAG3, TOX, PD1 expression). In vivo studies indicated that anti-CD47 treatment may suppress tumor growth, activate intra-tumoral cDC2 but not type 1 dendritic cells (cDC1), and delay CD8 T cells from entering terminal exhaustion in the tumor microenvironments. In vitro studies indicated that anti-CD47 may enhance the priming ability of cDC2, but not cDC1, and increase ISG15 expression in cDC2. When co-cultured with exhausted T cells, anti-CD47-treated cDC2 may delay the exhaustion process and restore antigen-specific effector function and cytotoxic capacity. Conclusion: Anti-CD47 may enhance antitumor T cell function in mouse liver cancer models by activation of cDC2, which may serve as a new strategy of developing immunotherapeutic agents for liver cancer (supported by grants NSTC 111- 2314-B-002-039 and 113-2314-B-002-113-MY3).
Citation Format: Cheng-Zhe Jian, Da-Liang Ou, Chia-Lang Hsu, Chien-Kuo Lee, Chiun Hsu. Activation of conventional type 2 dendritic cells (cDC2) by anti-CD47 may enhance antitumor T cell function in mouse liver cancer models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A047.
Abstract A050: Unraveling Immune Dysregulation in Acute Myeloid Leukemia: Insights from Whole Exome and Transcriptome Analysis
Authors: GOEL HARSH , Tanwar Pranay 
Published: October 2024

Abstract
Background: Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of myeloid progenitor cells. This study aims to elucidate genetic and transcriptomic alterations in AML through whole exome sequencing (WES) and transcriptome analysis, linking these findings with regulatory networks in hematopoiesis and immunology. Methods: We performed WES and transcriptome analysis on 10 AML samples to identify genetic mutations and expression changes. Bioinformatics tools, including differential expression analysis, gene set enrichment analysis (GSEA), and pathway analysis, were used to identify critical genes and regulatory networks. Comparative analyses with hematopoietic stem cells (HSCs) and immune cell subsets were conducted. Single-cell RNA sequencing (scRNA-seq) data were analyzed to delineate cellular heterogeneity and lineage differentiation pathways affected in AML. Results: Integrative analysis revealed key transcription factors and epigenetic regulators, such as RUNX1, FLT3, CEBPA, TP53, WT-1, GATA2, and TET2, frequently mutated or dysregulated in AML. Differential expression analysis identified distinct gene expression signatures in AML cells compared to normal HSCs, highlighting disruptions in cell cycle regulation, differentiation, and apoptosis. Altered immune regulatory pathways, including IL-7R and PD-1, indicated disruptions in immune cell activation and homeostasis. Single-cell analysis highlighted the cellular diversity and plasticity in AML. Conclusion: Our integrative bioinformatics approach links genetic and transcriptomic alterations in AML with disruptions in hematopoiesis and immune function. Key regulators and pathways identified offer potential therapeutic targets and deepen understanding of AML pathogenesis.
Citation Format: HARSH GOEL, Pranay Tanwar. Unraveling Immune Dysregulation in Acute Myeloid Leukemia: Insights from Whole Exome and Transcriptome Analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A050.
Abstract A051: Bitter agonists increase macrophage phagocytosis of head and neck squamous cell carcinoma cells
Authors: Hill Brianna L , Sywanycz Sarah M , Miller Zoey A , Lee Robert J , Carey Ryan M 
Published: October 2024

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 7th most commonly diagnosed cancer worldwide and is expected to increase in incidence by 30% by 2030. The HNSCC microenvironment is characterized by substantial macrophage infiltration. However, tumor-associated macrophages often cultivate an immunosuppressive environment that aids tumor progression. Previous work has shown that macrophages express bitter taste receptors (T2Rs), a class of GPCRs that can be activated with bitter compounds. Previous work has also demonstrated that stimulation of T2Rs in macrophages with bitter agonists, such as denatonium benzoate, increases phagocytosis of bacteria, but the impact of bitterants on macrophage phagocytosis of tumor cells is unknown. The goal of this study was to assess the impact of bitter compounds on macrophage phagocytosis of HNSCC cells in vitro. Human peripheral blood mononuclear cells obtained from healthy donors were used to generate monocyte-derived macrophages (MDMs). To investigate the effects of bitter agonist stimulation on macrophage phagocytosis, CFSE-labeled MDMs and DAPI-labeled HNSCC cell line SCC47, were co-stimulated with denatonium benzoate, and macrophage phagocytosis was quantified. This revealed that treatment with denatonium benzoate led to a 70% increase in macrophage phagocytosis compared to controls. Additional analysis revealed a 1.8-fold increase in F-actin in MDMs in response to denatonium benzoate measured via CellMask™ Actin staining, and that macrophages had generated F-actin positive tunneling nanotubes (TNTs). Further characterization with live cell imaging showed that these TNTs were being utilized as a means of mitochondrial transfer as observed by MitoTracker™ and CellMask™ Actin staining. Furthermore, there was a 2.5-fold decrease in mitochondrial ATP production in MDMs stimulated with denatonium benzoate, possibly indicating metabolic reprogramming. Timelapse imaging of MDMs demonstrated a reduction in mitochondrial ATP production, with a concomitant increase in F-actin production. These observations were confirmed in Phorbol 12-myristate 13-acetate differentiated THP-1 cells. Taken together, these results indicate that bitter taste receptor stimulation may contribute to a more activated macrophage phenotype denoted by a decrease in mitochondrial ATP production, increased F-actin staining, and increased phagocytosis of tumor cells.
Citation Format: Brianna L Hill, Sarah M Sywanycz, Zoey A Miller, Robert J Lee, Ryan M Carey. Bitter agonists increase macrophage phagocytosis of head and neck squamous cell carcinoma cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A051.
Abstract B001: Removal of interstitial hyaluronan facilitates subcutaneous administration and lymphatic delivery of anti-CTLA4 antibody and improves anti- tumor efficacy
Authors: Gracia Gracia , Cao Enyuan , Yuen Daniel , Ferreira Vilena DM , Chen Moore Z , Senyschyn Danielle , Mintern Justine D , Johnston Angus PR , Kang David W , Feeney Orlagh M , Porter Christopher JH 
Published: October 2024

Abstract
The tumor-draining lymph node (TDLN) modulates anti-tumor immunity. Targeting immune checkpoint blockade monoclonal antibodies (mAbs) to the TDLN via subcutaneous (SC) delivery has the potential to enhance efficacy and safety. Recombinant human hyaluronidase (rHuPH20; PH20) transiently removes hyaluronan at interstitial injection sites and is used to facilitate SC delivery of the large doses and volumes required for mAbs. We have previously shown that PH20 co-dosing improves the rate and extent of lymphatic absorption of SC mAbs. Here we investigate whether PH20 co-dosing improves the anti-tumor efficacy of SC anti-CTLA4 (αCTLA4) which targets T cell activation at the TDLN. Efficacy studies and immunophenotyping of the tumor and TDLN were conducted in syngeneic murine tumor models CT26/HAS and MC38/OVA. SC delivery significantly enhanced TDLN uptake of αCTLA4 compared to IV delivery and this was enhanced further by PH20 co-dosing. SC αCTLA4 ± PH20 also more effectively inhibited tumor growth than IV αCTLA4. Importantly, consistent with higher mAb uptake into the TDLN, SC delivery with PH20 enabled a reduction in αCTLA4 dose compared to SC alone or IV (similar efficacy at 3 to 8-fold lower doses). Efficacy improvements occurred concomitantly with greater, more sustained levels of cytotoxic effector CD8+ T cells at the tumor and CD62L+ stem-like CD8+ T cells at the TDLN. The efficacy advantage of SC delivery ± PH20 over IV was limited to TDLN- targeted mAbs. Combination therapy with a non-TDLN targeted mAb, αTIM3, was similarly efficacious across all dose routes. Overall, we report the potential utility of PH20 to improve TDLN-targeted immune checkpoint blockade beyond application as a SC administration enabler.
Citation Format: Gracia Gracia, Enyuan Cao, Daniel Yuen, Vilena DM Ferreira, Moore Z Chen, Danielle Senyschyn, Justine D Mintern, Angus PR Johnston, David W Kang, Orlagh M Feeney, Christopher JH Porter. Removal of interstitial hyaluronan facilitates subcutaneous administration and lymphatic delivery of anti-CTLA4 antibody and improves anti- tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B001.
Abstract B005: Denosumab Enhances Cytotoxic T Cell Infiltration by supressing SPP1 Expression in Giant Cell Tumour of Bone
Authors: Su Zezhuo , Fai Yeung Maximus Chun , Yin CHEUNG Jason Pui , Chi Cheung Kelvin Sin 
Published: October 2024

Abstract
Denosumab, a RANKL inhibitor, is primarily used to prevent osteoclastogenesis for the treatment of conditions like osteoporosis, bone metastasis, and giant cell tumor of bone (GCTB). RANKL is also key in immunity, activating NFκB and its target genes, including the osteopontin-coding gene SPP1, which is linked with CXCL9:SPP1 macrophage polarization and prognosis. Retrospective studies of bone metastasis have demonstrated improved clinical outcomes when immune checkpoint inhibitors (ICIs) are combined with denosumab. We undertook a study to explore denosumab's direct role in anti-tumor immunity. Single-cell RNA sequencing was performed on nine primary human GCTB samples, including three untreated and six treated solely with denosumab, to exclude confounding treatment factors linked with bone metastasis samples. Furthermore, we utilized immunohistochemistry staining from paired pre- and post-denosumab treated samples from a cohort of nine GCTB patients and conducted pan-cancer analysis on primary tumors, spanning 31 distinct types of cancers, sourced from the Genomic Data Commons Data Portal. Our single-cell analysis of GCTB resulted in a comprehensive cell atlas of this rare disease, revealing denosumab's role in inhibiting SPP1 expression and augmenting cytotoxic T cell infiltration. This was confirmed in nine pairs of pre- and post-denosumab treated GCTB samples using immunohistochemistry staining. The pan-cancer analysis indicated a negative correlation between SPP1 expression and CD8A levels across most tumor types, with the CD8A/SPP1 ratio correlating with clinical outcomes in 14 cancer types. Our research provides robust clinical evidence that denosumab improves anti-tumor immunity by inhibiting SPP1 expression, presenting a significant step towards patient selection for combined ICI and denosumab therapy.
Citation Format: Zezhuo Su, Maximus Chun Fai Yeung, Jason Pui Yin CHEUNG, Kelvin Sin Chi Cheung. Denosumab Enhances Cytotoxic T Cell Infiltration by supressing SPP1 Expression in Giant Cell Tumour of Bone [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B005.
Abstract B006: Ceralasertib enhance efficacy of anti-PDL1 treatment by modulating the tumor microenvironment in a IFNAR I dependent manner.
Authors: Sanseviero Emilio , Taylor Devon , Tohumeken Sehmus , Mai Mimi , Mostafa Ali , Milo Marta , Mulgrew Kathy , Fuchs Serge , Lau Alan , Barry Simon , Cobbold Mark , Gabrilovich Dmitry 
Published: October 2024

Abstract
This study is aimed to investigate the effect of ATR inhibitor (ATRi) ceralasertib on tumor microenvironment (TME). Ceralasertib has demonstrated encouraging clinical benefits in patients with non-small cell lung cancer who were resistant to PD1/PDL1 treatment. Using different pre-clinical mouse tumor models, we found that antitumor effect of ceralasertib was dependent on CD8 T cells. In fact, depletion of CD8 cells abrogated therapeutic effect of the ATRi. Ceralasertib treatment caused pleotropic effect in TME. It improved the function of T cells, depleted tumor associated macrophages and monocytic myeloid-derived-suppressor cells (MDSC) and inactivated suppressive activity of PMN-MDSC. Ceralasertib treatment resulted in activation of dendritic cells (DC) in tumor-bearing mice. DCs demonstrated increased ability to stimulate T cells, that resulted in enhanced antigen-specific T cell responses in mice treated with ceralasertib in combination with anti-PDL1. Gene expression profile showed significant up-regulation of type I interferon (IFN1) pathway in mice and patients treated with ceralasertib. Using BM chimera mice reconstituted with IFANR1KO for or IFNAR1SA bone marrow we demonstrated a cancelation of antitumor effect, or an enhancement of antitumor effect respectively induced by ceralasertib or combination therapy. DC cells isolated from IFNAR1KO mice treated with Ceralasertib failed to show an activated phenotype and to increase T cell activation demonstrating the pivotal role of type I IFN in ceralasertib-mediated immune activation. In conclusion, our finding showed that ATR inhibitor ceralasertib has a second mechanism of action necessary for its efficacy: modulating the tumor immune microenvironment and increasing sensitivity to anti-PDL1 treatment.
Citation Format: Emilio Sanseviero, Devon Taylor, Sehmus Tohumeken, Mimi Mai, Ali Mostafa, Marta Milo, Kathy Mulgrew, Serge Fuchs, Alan Lau, Simon Barry, Mark Cobbold, Dmitry Gabrilovich. Ceralasertib enhance efficacy of anti-PDL1 treatment by modulating the tumor microenvironment in a IFNAR I dependent manner [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B006.
Abstract B009: Enhancing Antitumor Immune Responses: Trastuzumab Deruxtecan (T- DXd) Induces Immunogenic Cell Death and Phagocytosis, Synergizing with CD47/SIRPα Checkpoint Blockade
Authors: Tsao Li-Chung , Wang John S. , Ma Xingru , Sodhi Sirajbir , Lyerly Herbert Kim , Hartman Zachary C. 
Published: October 2024

Abstract
Trastuzumab deruxtecan (T-DXd), or fam-trastuzumab-deruxtecan-nxki, is a novel antibody-drug conjugate (ADC) targeting HER2 that has demonstrated profound clinical efficacy across HER2-positive breast cancers (BC) and other cancers. However, the precise mechanisms underlying its superiority over traditional ADCs, such as trastuzumab emtansine (T-DM1), remain poorly understood. In this study, we investigated the immune activation mechanisms mediated by T-DXd cytotoxicity in HER2-positive BC. We found that the T-DXd payload, Deruxtecan (DXd), induces a stronger tumor immunogenic cell death (ICD) phenotype compared to T-DM1. This is evidenced by the elevated release of multiple Damage-Associated Molecular Patterns (DAMPs) and the activation of nearby myeloid immune cells through TLR4 and STING pathways. Additionally, T-DXd’s antibody backbone engages with Fcγ-receptors to stimulate Antibody-Dependent Cellular Phagocytosis (ADCP), similar to trastuzumab. Coupled with DXd-induced ICD, T-DXd enhances tumor antigen uptake by macrophages and stimulates antigen-specific CD8+ T cells better than T-DM1. Importantly, DXd cytotoxicity also upregulates tumor CD47 expression, which engages with SIRPα to suppress ADCP. To assess the importance of this regulatory axis in T- DXd efficacy, we explored the use of CD47/SIRPα checkpoint blockade antibodies in combination with T-DXd. Our in vivo studies revealed that this combination synergistically enhanced anti-tumor efficacy in a HER2-transgenic BC mouse model, while inducing CD8+ T cell immune memory and preventing tumor recurrence after therapy cessation. In sum, these studies highlight the important role of T-DXd in stimulating innate and adaptive immune responses against HER2-positive BC and demonstrate the enhancement of this anti-tumor mechanism through combination with CD47/SIRPα checkpoint blockade.
Citation Format: Li-Chung Tsao, John S. Wang, Xingru Ma, Sirajbir Sodhi, Herbert Kim Lyerly, Zachary C. Hartman. Enhancing Antitumor Immune Responses: Trastuzumab Deruxtecan (T- DXd) Induces Immunogenic Cell Death and Phagocytosis, Synergizing with CD47/SIRPα Checkpoint Blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B009.