bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B048: Neutrophil extracellular traps-targeting DNase I enhances the therapeutic efficacy of CAR-T cell adoptive immunotherapy in a syngeneic murine metastasis model
Authors: Stepanov Alexey , Wang Wenjian , Hou Yingqin , Ivan Chernikov Ivan Chernikov , Bissonnette Reid , Tetz George , Borisenko Grigory , Genkin Dmitry 
Published: November 2024

Abstract
In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising approach for treating various malignancies, most notably in hematologic cancers. However, its efficacy in solid tumors is often hindered by an immunosuppressive tumor microenvironment (TME), which, in particular, is frequently characterized by the presence of tumor-associated cell-free DNA (cfDNA), especially in the form of neutrophil extracellular traps (NETs). In adoptive immunotherapies NETs, composed primarily of neutrophil-derived DNA, histones and neutrophil granule enzymes (e.g., MPO, NE), act as physical barriers and induce the secretion of immunosuppressive factors that impair CAR T cell function. This study investigates the potential of co-administration of deoxyribonuclease I (DNase I) with CAR T cells in a syngeneic B16 melanoma murine model of lung metastasis. Bioluminescent imaging of melanoma metastatic processes has shown that a single injection of DNase I (10 mg/kg) suppresses B16-EGFR lung metastasis at early stages in comparison to the vehicle control group but does not improve survival. However, co-administration of DNase I with murine EGFR-CAR T cells significantly suppresses tumor burden, decreases the number of metastatic foci, and substantially prolongs survival compared to the CAR T cell monotherapy group. Degrading of NETs [RB1] by DNase I increases the amount of tumor-infiltrating T and CAR T cells and reduces the immunosuppressive effects of the TME. This is reflected in the CD8 population of tumor-infiltrating CAR T cells from the DNase I treated group, which have lower expression of PD-1 and TIM-3 exhaustion markers. This research highlights the critical role of the NETs in modulating CAR T cell efficacy and provides a compelling rationale for incorporating DNase I as an adjunctive treatment to improve therapeutic responses in patients undergoing CAR T cell therapy. However, further clinical studies are warranted to validate these findings and explore the translational potential of this combinatorial approach in enhancing cancer treatment. [RB1]Again - this takes the emphasis and the reader away from NETs and into the cfDNA universe.
Citation Format: Alexey Stepanov, Wenjian Wang, Yingqin Hou, Ivan Chernikov Ivan Chernikov, Reid Bissonnette, George Tetz, Grigory Borisenko, Dmitry Genkin. Neutrophil extracellular traps-targeting DNase I enhances the therapeutic efficacy of CAR-T cell adoptive immunotherapy in a syngeneic murine metastasis model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B048.
Abstract C002: CKLF attracts CCR4-expressing CD4+ cells to foster immune repression and tumor aggressiveness in MYCN-driven neuroblastoma
Authors: Qin Xiaodan , Feng Hui , Lam Andrew , Zhang Xu , Sengupta Satyaki , Iorgulescu Bryan , Das Sanjukta , Zhou Zhenwei , Zuo Tao , Meara Grace , Rager Madison , Floru Alexander , Ni Hongru , Kemet Chinyere , Veerapaneni Divya , Kashy Daniel , Lin Liang , Lloyd Kenneth , Kwok Lauren , Smith Kaylee , Nagaraju Raghavendar , Meijers Rob , Ceol Craig , Liu Ching-Ti , Alexandrescu Sanda , Wu Catherine J. , Keskin Derin , George Rani 
Published: November 2024

Abstract
Neuroblastoma, especially those with aberrant MYCN activation, often harbor an immunosuppressive microenvironment to fuel malignant growth and trigger treatment resistance. Despite this knowledge, there are no effective strategies to tackle this problem. Here we combined analyses of human neuroblastoma with live tracking and functional studies of the tumor microenvironment (TME) in zebrafish. We identified chemokine-like factor (CKLF) as a key driver of MYCN-mediated immunosuppression and neuroblastoma aggression. We showed that human MYCN-activated neuroblastoma upregulates and secretes CKLF, which is a reliable predictor of poor patient survival. Analysis of primary patient samples demonstrates a strong positive association between MYCN and CKLF expression in neuroblastoma cells together with the enrichment of FOXP3+ T cells in the TME. Taking advantage of in vivo zebrafish models of MYCN-driven neuroblastoma that resemble human high-risk disease, we demonstrated that cklf overexpression in zebrafish neural crest cells induces an immunosuppressive TME while promoting rapid tumor onset and progression. We also demonstrated that as early as the premalignant stage, tumor cells secrete CKLF to attract CCR4-expressing Cd4+ cells to induce immunosuppression and tumor aggression. Conversely, genetic depletion of cklf in tumor cells reduces the recruitment of Cd4+ cells to the TME while increasing cytotoxic Cd8+ and natural killer cells infiltration, inhibiting neuroblastoma development in zebrafish. Our work provides the first example that MYCN can activate CKLF to allure CD4+ immune cells to the TME and incite immunosuppression, positioning CKLF as a potential novel immunotherapeutic target for the treatment of MYCN-driven high-risk neuroblastoma.
Citation Format: Xiaodan Qin, Hui Feng, Andrew Lam, Xu Zhang, Satyaki Sengupta, Bryan Iorgulescu, Sanjukta Das, Zhenwei Zhou, Tao Zuo, Grace Meara, Madison Rager, Alexander Floru, Hongru Ni, Chinyere Kemet, Divya Veerapaneni, Daniel Kashy, Liang Lin, Kenneth Lloyd, Lauren Kwok, Kaylee Smith, Raghavendar Nagaraju, Rob Meijers, Craig Ceol, Ching-Ti Liu, Sanda Alexandrescu, Catherine J. Wu, Derin Keskin, Rani George. CKLF attracts CCR4-expressing CD4+ cells to foster immune repression and tumor aggressiveness in MYCN-driven neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C002.
Abstract C003: Outer membrane vesicles from Bacteroides fragilis contain coding and non-coding small RNA species that modulate inflammatory signaling in intestinal epithelial cells
Authors: Sheikh Aadil , Scano Colin , Xu Julia , Ojo Tolulope , Conforti Jessica M. , Haberman Kayla L. , King Bryan , Lotter James , Martinez Alysia , Ojeas Harry , Pujol Michelle , Watkins Juli , Lin Emily , Zechmann Bernd , Sevcik Amanda , Sayes Christie , Gallagher Elyssia S , Mell Joshua , Ehrlich Garth , Taube Joseph H , Greathouse K. Leigh 
Published: November 2024

Abstract
Alterations to the community structure and function of the microbiome are associated with changes to host physiology, including immune responses. However, the contribution of microbial-derived RNAs carried by outer membrane vesicles (OMVs) to host immune responses remains unclear. This paper investigates the role of OMVs and OMV-associated small RNA (sRNA) species from pathogenic and commensal Bacteroides fragilis (ETBF and NTBF respectively) in eliciting different immune responses in intestinal epithelial cells. To distinguish the differences in the sRNA profiles of both strains and their OMVs, small RNA-seq was conducted, and identified enrichment of discrete sRNA species in OMVs that were also differentially expressed between the two strains. To understand the effects of OMVs on pattern recognition receptors, Toll-like receptor (TLR) reporter cells were treated with OMVs, and activation of TLRs 2, 3, 4, and 7 were observed. Treatment of Caco-2 and HT29-MTX cells with OMVs demonstrated increased expression of IL-8. Surprisingly, we discovered that degradation of RNase-accessible RNAs within ETBF OMVs, but not NTBF OMVs, resulted in vesicles with enhanced capacity to stimulate IL-8 expression, indicating that these extravesicular RNAs exert an immunosuppressive effect. This suggests a dual role for OMV-associated RNAs in modulating host immune responses, with implications for both bacterial pathogenesis and therapeutic applications.
Citation Format: Aadil Sheikh, Colin Scano, Julia Xu, Tolulope Ojo, Jessica M. Conforti, Kayla L. Haberman, Bryan King, James Lotter, Alysia Martinez, Harry Ojeas, Michelle Pujol, Juli Watkins, Emily Lin, Bernd Zechmann, Amanda Sevcik, Christie Sayes, Elyssia S Gallagher, Joshua Mell, Garth Ehrlich, Joseph H Taube, K. Leigh Greathouse. Outer membrane vesicles from Bacteroides fragilis contain coding and non-coding small RNA species that modulate inflammatory signaling in intestinal epithelial cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C003.
Abstract C005: Tumor vaccines and oncolytic virotherapy: systemic immunity vs. tumor microenvironment
Authors: Jia William 
Published: November 2024

Abstract
Tumor vaccines, particularly the innovative mRNA variants, hold immense promise in cancer immunotherapy. Despite their potential, these vaccines encounter formidable challenges in surmounting immune tolerance, the immune-suppressive tumor microenvironment (TME) and more importantly, the resistance developed in cancer cells that are antigen negative. Concurrently, oncolytic virotherapy (OV), a distinct facet of tumor vaccination, significantly alters the TME and releases tumor antigens via lysis to generate a broader spectrum of tumor antigens. This unique property positions OV to induce anti-tumor immunity, as evidenced by prolonged overall survival and abscopal tumor suppression. Recognizing the complementary strengths of mRNA tumor vaccines and OV, we propose a combined approach to address the limitations inherent in each modality. Our study tested this hypothesis by combining a mRNA vaccine targeting HER2 with oncolytic viruses, utilizing a prime-boost strategy on a HER2-expressing CT26 mouse tumor model. Notably, while the mRNA vaccine alone induced specific anti-HER2 systemic immunity, the combination demonstrated a potent immune response against both anti-HER2 and anti-CT26, leading to durable tumor eradication. Our findings highlight that peripheral vaccination has the potential to elicit an immune response in non-immune suppressive environments. However, combining it with virotherapy not only amplifies specific immunity but also induces a broader immune response against a spectrum of tumor antigens. This synergistic combination represents a promising avenue for advancing cancer immunotherapy, offering the potential for improved treatment outcomes and broader applicability of tumor vaccines across diverse cancer types.
Citation Format: William Jia. Tumor vaccines and oncolytic virotherapy: systemic immunity vs. tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C005.
Abstract C008: New insights from a novel mouse model of synovial sarcoma
Authors: Mohei Hesham , Van Deren Donn , Molina Irene S. , Haldar Malay 
Published: November 2024

Abstract
Mouse models are the basis of preclinical and translational research in solid tumors. Multiple methods exist to induce tumor formation in mice, including genetically engineered mouse models, chemotoxic agents, injection of tumor cells, and xenograft approaches. Synovial sarcoma, a rare highly malignant soft-tissue tumor, poses a serious threat to patients due to its aggressive nature and associated high rates of mortality and morbidity. This disease's underlying cause and development remain poorly comprehended, and existing treatment approaches have yielded unsatisfactory outcomes. In the last two decades, numerous effective animal models of soft tissue sarcoma (STS) have been created, primarily utilizing genetically engineered mice and zebrafish, however long latency of tumor development for several months in these models creates a barrier for practical in-vivo experiments for drug testing or manipulating the cellular composition of the tumor microenvironment. In studying cancer immunotherapy, it is important to consider aspects of antitumor immune responses and to produce a model that mimics the complexity of the immune system We have generated a new mouse model of synovial sarcoma of exceptionally fast tumor development. Intramuscular delivery of Cre recombinase protein in mice which drives conditional knockdown in PTEN, stabilization of β-catenin, and formation of fusion oncogenes of SS18-SSX2 was sufficient to initiate high-grade synovial sarcomas with myofibroblastic differentiation in 3 weeks. As immunotherapy is increasingly applied to sarcomas, our mouse model will serve as a great tool for preclinical data. Flow cytometry-based analysis of peripheral blood shows significant changes in immune cell populations as early as five days after Tat-Cre injection and continues throughout the development of synovial sarcoma. These results suggest a significant systemic phenotypic alteration of circulating immune cells, which may impact other major organs in this genetic mouse model of synovial sarcoma. Single- cell RNA sequencing of the CD45+ leukocytes in the tumor microenvironment reveals subsets that may promote tumor progression. Our work promises to significantly enhance our understanding of the pathogenesis of this disease and establish a reliable preclinical platform for devising and assessing therapeutic interventions.
Citation Format: Hesham Mohei, Donn Van Deren, Irene S. Molina, Malay Haldar. New insights from a novel mouse model of synovial sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C008.
Abstract C018: Awakened dormant cancer cells undergo highly mesenchymal to quasi- mesenchymal transition and acquire stemness
Authors: Zhang Jingwei , Weinberg Robert 
Published: November 2024

Abstract
The awakening of dormant disseminated cancer cells is likely responsible for the clinical relapses of patients whose primary tumors have been cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, non-proliferative phenotypic state. The awakening of these cells does not occur by a cancer cell-autonomous process. Instead, inflammation and wound healing of the surrounding tissue microenvironment causes them to shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire stemness and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their stemness, doing so without ongoing heterotypic signaling from the lung microenvironment. EGFR ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is essential for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.
Citation Format: Jingwei Zhang, Robert Weinberg. Awakened dormant cancer cells undergo highly mesenchymal to quasi- mesenchymal transition and acquire stemness [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C018.
Abstract C019: IL27R signaling regulates neutrophils maturation, activation and function in colorectal cancer-liver metastases
Authors: Zhu Jiani , Shi Zhengzheng , Koltsova Ekaterina 
Published: November 2024

Abstract
Colorectal cancer (CRC) is the third most common cancer and fourth cause of cancer death worldwide. The liver is the most common organ for CRC metastasis, which is a major cause of death for CRC patients. Therefore, a better understanding of mechanisms facilitating CRC liver metastasis is in urgent need. IL27 is a member of IL6/IL12 cytokines superfamily which have a critical role in tumor microenvironment to affect tumorigenesis and metastasis. IL27 is secreted by activated macrophages and dendritic cells, and IL27R is expressed in various immune cells, mediating IL27-dependent pro-inflammatory or anti-inflammatory immune responses. However, the role of myeloid IL27 signaling in CRC-liver metastasis remains unclear. To study the role of IL27R signaling in myeloid cells, we generated Il27ra fl/fl mice and crossed them with LysM cre deleter to obtain LysM cre+ Il27ra f/f mice. Using MC-38 CRC cells portal vein injection model, we found that myeloid IL27Ra deletion leads to increased CRC-liver metastasis accompanied by increase in neutrophils, particularly Ly6G+Cxcr2-CD101- immature neutrophils, in circulation as well as tumors in LysM cre+ Il27ra f/f mice. Single-cell sequencing of tumor-infiltrating immune cells revealed that lack of IL27Ra in myeloid cells promoted neutrophil recruitment and degranulation as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS) production but inhibited neutrophil maturation and production of pro-inflammatory chemokines and cytokines such as CXCL10, CSF1 and TNF. Furthermore, IL27Ra deficient neutrophils displayed heightened inflammatory response when stimulated with LPS in vitro. Collectively, our work reveals novel role of myeloid IL27Ra signaling that inhibits metastatic liver colonization by promoting neutrophil maturation, restricting neutrophil infiltration and degranulation.
Citation Format: Jiani Zhu, Zhengzheng Shi, Ekaterina Koltsova. IL27R signaling regulates neutrophils maturation, activation and function in colorectal cancer-liver metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C019.
Abstract C020: Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors
Authors: Das Indrani , Abiona Olubukola , Liu Riufu , Lee Grace K. , Wald David N. 
Published: November 2024

Abstract
While adoptive cellular therapies (ACT) such as CAR-T and NK therapy have shown clinical efficacy against hematologic malignancies, their use against solid tumors (such as ovarian or pancreatic cancer) has had limited success to date. In particular, CAR-T therapy for solid cancers has led to severe toxicities, including on-target, off-tumor killing of healthy cells and graft vs. host disease (GVHD) with allogeneic transplant. NK cell therapies, in contrast, have fewer associated toxicities due to specific and innate recognition/killing of cancer cells. This greater safety profile makes NK therapies an attractive treatment option for solid cancers. NK therapies are currently limited by insufficient in vivo tumor clearance, caused largely by their lower cytotoxicity and in vivo expansion compared to CAR-T cells. To address this, we have screened 300,000 small molecule compounds for their ability to enhance NK cytotoxicity against ovarian cancer (OVCAR) cells. Our primary screen identified 11 lead compounds which increase NK killing activity against OVCAR cells &gt;= 10% over baseline (vehicle-treated control). Secondary in vitro assays have confirmed that at least 3 out of 11 lead compounds enhance NK cytotoxicity by at least 10% over baseline. As such, we hypothesize that our lead compounds will increase in vivo NK cytotoxicity and tumor clearance, through mechanisms which might include I) upregulation of NK activating receptors, II) downregulation of NK inhibitory receptors, and/or III) modulation of NK metabolism in the immunosuppressive tumor microenvironment. Immediate future studies include in vivo testing of our lead compounds’ ability to enhance NK cytotoxicity, using immunodeficient mouse models of subcutaneous OVCAR tumors. Moreover, we will utilize 2D and 3D in vitro culture techniques alongside flow cytometry and RNA sequencing to identify how lead compounds impact markers of NK activation and metabolism. This will include expression of activating/inhibitory receptors, exhaustion markers, and key metabolic factors. Finally, we will assess the effect of lead compounds on NK function within an immunosuppressive tumor environment. Our findings will contribute to effective future NK cell therapies for solid tumors.
Citation Format: Indrani Das, Olubukola Abiona, Riufu Liu, Grace K. Lee, David N. Wald. Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C020.
Abstract C023: P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy
Authors: Zhou Lin , DeMarco Kelly D. , Murphy Katherine C. , Wu Zhenpeng , Li Jinping , Li Junhui , Johnson Calvin , Jiang Zhong , Bai Shi , Ye Tianyi , Simin Karl , Zhu Lihua Julie , Pitarresi Jason R , Wu Hong , Ruscetti Marcus 
Published: November 2024

Abstract
Cellular senescence is historically viewed as a tumor-suppressive cell cycle arrest program to limit outgrowth of pre-malignant cells. However, emerging evidence suggests senescent cell persistence contributes to immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find that p16+ senescent cells accumulate throughout malignant progression and are associated with immune suppression and poor survival. p16 ablation in mice eliminated senescent epithelial cells and reversed immune suppression mediated by immature myeloid cells but not prostate tumorigenesis. Single cell sequencing revealed an additional population of senescent p21+ fibroblasts and myeloid cells. Targeting BCL-xL or PD-L1 induced during senescence could remove both p16+ epithelial and p21+ stromal senescent cells, reactivate T cell immunity, and block tumor initiation as well as progression in advanced prostate cancer models. Our findings demonstrate that targeting heterogenous senescent populations can not only prevent malignant transformation but also yield therapeutic benefits in advanced prostate cancers through activating anti-tumor immunity.
Citation Format: Lin Zhou, Kelly D. DeMarco, Katherine C. Murphy, Zhenpeng Wu, Jinping Li, Junhui Li, Calvin Johnson, Zhong Jiang, Shi Bai, Tianyi Ye, Karl Simin, Lihua Julie Zhu, Jason R Pitarresi, Hong Wu, Marcus Ruscetti. P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C023.