bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1340: Modulation of the natural killer cell immune response to tumor with a synthetic tumor -immune cell agonist, NK-TICA™
Authors: Dufort Fay , Ezell Tucker , Rezvaya Alexandra , Ho Kathleen , Leitheiser Christopher , Brandish Philip , McDonnell Kevin , Keen Nicholas 
Published: March 2024

Abstract
Natural Killer (NK) cells are highly responsive cytotoxic immune cells of the innate immune system with well characterized anti-tumor properties. Their ability to directly kill malignant cells and elicit an adaptive immune response makes them a promising candidate for a precision guided immunotherapy in oncology. Bicycle® peptides are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle® platform technology to discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA™). The NK-TICA™ consists of chemically coupled Bicycle® peptides that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell function. We demonstrate potent, selective binding of our Bicycle® peptides to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA™ compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner. In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle® NK-TICA™ as a multifunctional immune cell engager will promote the modulation and anti-tumor activity of peripheral and intra-tumoral NK cells to solid tumors.
Citation Format: Fay Dufort, Tucker Ezell, Alexandra Rezvaya, Kathleen Ho, Christopher Leitheiser, Philip Brandish, Kevin McDonnell, Nicholas Keen. Modulation of the natural killer cell immune response to tumor with a synthetic tumor -immune cell agonist, NK-TICA™ [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 1340.
Abstract 1343: BSI-111, a highly selective anti-CD16a monoclonal antibody with potent agonist activity for building a NK cell engager platform
Authors: Liu Jinyu , Dai Wenwen , Li Hongyan , Liu Xiaodong F. , Li Jun , Xia Shukai , Lyu Qun , Davis Hugh M. , Chen Mingjiu , Peng Zeyu 
Published: March 2024

Abstract
Background: Natural killer cells (NK) are innate lymphocytes endowed with the ability to recognize and kill cancer cells. CD16a, a well-characterized activating receptor predominantly expressed on NK cells, is a low-affinity receptor for the IgG Fc domain and is crucial for stimulating NK cell-mediated tumor cell killing. Unlike CD16a, CD16b is mainly expressed on granulocytes as a GPI-anchored receptor and is not involved in the lysis of tumor cells although CD16a and CD16b share 97% sequence identity in their extracellular domains. Due to the high homology of extracellular domains of CD16a and CD16b, it is extremely challenging to develop CD16a-specific agonistic antibodies without binding CD16b+ granulocytes, the most abundant subset in leukocytes. Here we report the development of an anti-CD16a-specific monoclonal antibody with potent NK cell activation.
Experimental procedures: Humanized mice were immunized with recombinant CD16a-ECD-Fc. The Biosion proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify an anti-CD16a monoclonal antibody lead candidate - BSI-111. The target binding specificity, binding activity, and affinity of BSI-111 were evaluated by protein-based ELISA, cell-based FACS and Biacore-based SPR. A cell-based agonist reporter assay and a primary NK cell activation assay were used to evaluate the bioactivity of BSI-111.
Summary: BSI-111 is a fully human monoclonal antibody with the following critical properties: (1) specifically binds to CD16a without recognizing CD16b; (2) binds the two allelic variants of CD16A - 158F and 158V with similar high affinities; (3) shows cross-reactivity to cynomolgus CD16a; (4) can significantly activate NFAT signaling in a cell-based reporter assay; (5) exhibits strong activity on activating primary NK cells; and (6) has potentially longer half-life and silenced Fc-effector function through Fc-engineering.
Conclusion: BSI-111 demonstrates great biophysical properties and functional characteristics, supporting the development of anti-CD16a-based NK cell engagers for potential benefit of cancer patients.
Citation Format: Jinyu Liu, Wenwen Dai, Hongyan Li, Xiaodong F. Liu, Jun Li, Shukai Xia, Qun Lyu, Hugh M. Davis, Mingjiu Chen, Zeyu Peng. BSI-111, a highly selective anti-CD16a monoclonal antibody with potent agonist activity for building a NK cell engager platform [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 1343.
Abstract 1345: NAV-201, an orally bioavailable small molecule NK cell activator enhancing antibody-mediated cancer therapies
Authors: Nicolaides Nicholas C. , Grasso Luigi , Kline J. Brad 
Published: March 2024

Abstract
Tumors employ a number of mechanisms to suppress a patient’s immune anti-tumor responses. Recently, we uncovered an immunosuppression mechanism that tumors employ to avoid humoral immune responses that involves tumor-produced proteins, called Humoral Immuno-Oncology (HIO) factors. These HIO factors are able to suppress antibody-mediated tumor cell killing via direct binding to antibodies that alter their Fc domain interactions with the C1q protein to suppress complement dependent cytotoxicity (CDC) and reduce antibody engagement with CD16a Fc receptors on immune-effector cells, including NK cells, to suppress antibody dependent cellular cytotoxicity (ADCC). HIO factor immunosuppression of ADCC appears to involve the reduced binding affinity of antibody to CD16a Fc receptors. In an attempt to identify agents that may enhance antibody-CD16a binding affinity to overcome HIO factor immunosuppression, we sought to identify agents that can restore this interaction by screening natural small compound libraries via an IgG1-CD16a based ELISA assay. One lead compound was identified that was subsequently optimized by structural activity relationship analysis. This compound, named NAV-201, specifically binds CD16a and enhances the affinity of antibody binding to both the low affinity CD16a-158F and high affinity CD16a-158V allotypes. Moreover, we found that NAV-201 can also bind to the mouse CD16a ortholog and enhance its antibody binding affinity, making NAV-201 suitable for efficacy testing in mouse models. In vivo, NAV-201 was found to be well tolerated up to at least 120 mg/kg when administered orally and daily to mice, have a serum half-life of 18 hours, enhance systemic levels of the NK cell produced INF-γ and TNF-α cytokines, and enhance the therapeutic efficacy of antibodies in mouse xenografts. Together, these data support the further development of NAV-201 for human testing to improve and/or enhance the efficacy of antibody-based therapies in HIO factor positive cancers.
Citation Format: Nicholas C. Nicolaides, Luigi Grasso, J. Brad Kline. NAV-201, an orally bioavailable small molecule NK cell activator enhancing antibody-mediated cancer 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 1345.
Abstract 1374: Targeting CD47/SIRPɑ axis in urologic cancer triggers enhanced phagocytosis of tumor cell and induces tumor growth inhibition
Authors: Shen Fan , Praharaj Monali , Lee Alex J. , Nirschl Thomas R. , Wang Xiaoxu 
Published: March 2024

Abstract
Signal regulatory protein-α (SIRPα; CD172a or SHPS-1) is a transmembrane molecule that highly expressed on myeloid population. Binding of CD47 (integrin-associated protein, IAP) to SIRPα inhibits phagocytosis in macrophages, which acts as a mechanism of maintaining homeostasis. Tumor cells however, often time upregulate CD47 to evade immune response. Using publicly available dataset, we found that human prostate cancer cells upregulate expression of both CD47 and calreticulin, a “eat me” signal when engaged with Low density lipoprotein receptor-related protein 1 (LRP1). In addition, macrophages, monocytes and dendritic cells in human prostate cancer do have relatively high level of SIRPɑ and LRP1 expression. This finding provides the rationale of targeting CD47/SIRPɑ axis in prostate cancer to shift the balance between pro-phagocytosis and anti-phagocytosis signaling. We then moved to RM1 and B6Cap, two syngeneic prostate cancer models in immunocompetent mice. Significant tumor growth inhibition was seen in both models with anti SIRPɑ blocking antibody. Furthermore, we observed in vitro that CD47 or SIRPɑ blockage led to enhanced PC3 cell line phagocytosis by human monocyte derived macrophages (HMDMs). Same finding was found using mouse bone marrow derived macrophages (BMDMs). We then utilized ovalbumin expressing MB49 bladder cancer cell line and cocultured those with BMDMs. CD8+ T cell from OT1 mice exhibited higher expression of activation makers when cocultured BMDMs treated by either anti CD47 or SIRPɑ antibody, indicating that enhanced phagocytosis subsequently increases antigen cross presentation in macrophages. In summary, we identified that CD47 is overexpressed in human prostate cancer; blocking CD47/SIRPɑ did inhibit tumor growth through enhanced phagocytosis and antigen presentation.
Citation Format: Fan Shen, Monali Praharaj, Alex J. Lee, Thomas R. Nirschl, Xiaoxu Wang. Targeting CD47/SIRPɑ axis in urologic cancer triggers enhanced phagocytosis of tumor cell and induces tumor growth inhibition [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 1374.
Abstract 1385: Crosstalk between hepatocyte and myeloid-specific IL17 signaling in colorectal cancer metastasis
Authors: Chojnacka Katarzyna , Kamen Dan , Reyes Katrina M. , Tomizawa Hana , Grivennikov Sergei I. 
Published: March 2024

Abstract
Advanced colorectal cancer (CRC) is resistant to current immunotherapies and prone to metastasis. Chronic inflammation mediated by cytokines such as interleukin (IL)17 activates the oncogenic pathways in cancer cells, promoting sporadic and inflammation-associated CRC. Increased levels of IL17A in early stages of CRC portends poor prognosis indicating its potential involvement into metastasis. We and others previously showed that IL17A signaling is required for early CRC tumorigenicity in a variety of models and that in early CRC, its ability to signal to epithelial cells is essential. What remains unknown is whether IL17 signaling to other cell types within the tumor microenvironment (TME) is essential to control tumor progression and metastasis. Using a model of colitis-associated cancer (CAC) we found that “late” IL17A neutralization decreases tumor burden, possibly acting through regulation of myeloid cells and chemokine network essential for the control of immunosuppressive TME. Next, using models of colorectal cancer liver metastasis (CRLM) including intraportal cell injection and cecum transplantation of organoids with distinct set of oncogenic mutation we found that IL17 neutralization reduces metastasis. FACS analysis revealed that IL17A promotes the recruitment of tumor-associated macrophages and other key myeloid subsets into the metastatic liver environment. Interestingly, ablation of IL17RC (receptor) in myeloid cells only (using Il17rcf/f -LysMCre mice) led to reduction in metastasis and reshaping of metastatic myeloid cell compartments. Meanwhile, IL17 signaling in hepatocytes was required for early metastasis and pre-metastatic niche formation, as the ablation of IL17RC in hepatocytes (using Il17rcf/f -AlbCre mice) led to a reduction of metastatic numbers but not growth. This coincided with reduced neutrophil recruitment and enhanced activation of cytotoxic innate lymphoid cells and CD8 T lymphocytes, indicating the role of hepatocyte specific IL17 signaling in blunting anti-tumor immunity. Our findings illuminate the role of inflammatory cytokine IL17 into CRC progression and metastasis and imply its distinct cell type specific role within the metastatic liver TME.
Citation Format: Katarzyna Chojnacka, Dan Kamen, Katrina M. Reyes, Hana Tomizawa, Sergei I. Grivennikov. Crosstalk between hepatocyte and myeloid-specific IL17 signaling in colorectal cancer metastasis [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 1385.
Abstract 1386: CD1d-restricted iNKT cells promote liver metastasis from colon cancer
Authors: Nater Marc , Lucchiari Giulia , Brügger Michael , Valenta Tomas , Cecconi Virginia , Forni Geo , Benke Stephan , Broek Maries van den 
Published: March 2024

Abstract
The liver is a prominent site for metastasis, yet little is known about the role of liver immunity in antimetastatic defense. Compared to other organs, the liver harbors a unique immune environment characterized by the abundance of innate cell lineages, including CD1d-restricted invariant natural killer T (iNKT) cells. To investigate the influence of iNKT cells on metastasis, we established an orthotopic model of colorectal cancer (CRC) with spontaneous dissemination to the liver. We induce the primary tumor by implanting CRC organoids into the colon mucosa of syngeneic C57BL/6 mice, resulting in hepatic macrometastases within 5 weeks. We observed that liver metastasis hardly occurred in mouse strains lacking iNKT cells (Cd1d−/− and Traj18−/− mice), while the growth of the primary tumor was comparable to that in wild-type mice. These results indicate a tumor-promoting function for hepatic iNKT cells. We uncovered that hepatic iNKT cells respond to disseminating cancer by producing IL-4 and IL-13, two cytokines known to activate hepatic stellate cells (HSCs) into fibrogenic myofibroblasts. Indeed, we saw rapid activation of HSCs and deposition of extracellular matrix upon arrival of cancer cells in the liver of wild-type but not iNKT cell-deficient mice. We propose that hepatic iNKT cells contribute to the formation of a supportive niche for disseminated tumor cells by activating HSCs early in the development of hepatic metastasis. Taken together, our findings highlight an essential tumor-promoting role for iNKT cells during the development of liver metastasis and contribute to our understanding of immune regulation of metastasis.
Citation Format: Marc Nater, Giulia Lucchiari, Michael Brügger, Tomas Valenta, Virginia Cecconi, Geo Forni, Stephan Benke, Maries van den Broek. CD1d-restricted iNKT cells promote liver metastasis from colon cancer [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 1386.
Abstract 1387: SETD2 loss promotes macrophage infiltration and metastasis in RCC
Authors: Arner Emily N. , Wolf Melissa M. , Vlach Logan , Rathmell Jeffrey C. , Rathmell W. Kimryn 
Published: March 2024

Abstract
Across human cancer, tumors that are high grade, poorly differentiated, and have undergone epithelial-to-mesenchymal transition (EMT) carry a worse prognosis with a high likelihood of metastasizing to distant organs. Despite significant research efforts, metastatic cancers and relapse remain the primary cause of cancer related deaths. In renal cell carcinoma (RCC), metastasis is present in one-third of patients at the time of diagnosis, and one-third of patients who initially present with locally advanced disease eventually develop local or distant recurrence following resection of the primary tumor, highlighting the need for new RCC therapies and further insight into the metastatic process. Using RCC patient biopsies, we found that patients with more epithelial tumors have a significantly lower risk of recurrence. Additionally, tumors that had a mesenchymal protein signature had significantly increased macrophage infiltration, which was significantly associated with a higher stage at diagnosis and worse overall survival, suggesting that macrophages may play an important role in EMT and metastasis in ccRCC. Whole exome sequencing of these patient samples revealed that mutational loss of SETD2, a histone methyltransferase that is lost in about 20% of RCC patients, correlated strongly with increased macrophage infiltration within the primary tumor and was necessary for the correlation between macrophages and EMT. SETD2 loss in syngeneic kidney cancer mouse models confirmed that SETD2 loss within tumor cells resulted in increased EMT, macrophages within the primary tumor microenvironment (TME), and spontaneous metastasis, further supporting the role of macrophages in promoting metastasis in the absence of SETD2. Further characterization of the gene signatures and immune cell infiltrate in RCC will lead to a better understanding of metastasis in an oncogene- and tissue-specific manner and thus lead to more efficacious therapies for metastatic patients.
Citation Format: Emily N. Arner, Melissa M. Wolf, Logan Vlach, Jeffrey C. Rathmell, W. Kimryn Rathmell. SETD2 loss promotes macrophage infiltration and metastasis in RCC [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 1387.
Abstract 1389: Understanding the differential role of an IL-6 family cytokine in varying subtypes of breast cancer patients for novel therapeutic intervention
Authors: Wolf Cody L. , Tawara Ken , Jorcyk Cheryl L. 
Published: March 2024

Abstract
In the United States, it is estimated that over 295,000 women will be diagnosed with breast cancer, and over 43,000 breast cancer deaths in 2023. Mortality in breast cancer is due in large part due to distant metastasis to organs such as the bone, lung, liver, and brain. Our laboratory has identified that the IL-6-family cytokine oncostatin M (OSM) plays a crucial role in initiating metastasis by secreting pro-metastatic molecules such as VEGF, LOXL2 and IL-6, and increasing circulating tumor cell numbers and metastases to bone and lung in vivo. More recent work within our lab has identified unique roles for OSM in varying subtypes of breast cancer patients, particularly between estrogen receptor positive (ER+) and ER- patients. It is well known that patients with ER- breast cancer, specifically triple negative breast cancer (TNBC; ER- PR- HER2-), have limited therapeutic options. However, the divergent role OSM plays in ER+ and ER- breast cancer and the mechanism by which this occurs has yet to be fully understood. Thus, we aimed to fully elucidate the difference between OSM in ER+ versus ER- breast cancer. RNA sequencing analysis on OSM-treated human ER+ cells and ER- TNBC cells discovered significant differences in gene expression between both cell lines upon treatment with OSM, including alteration in DNA-replication and cell cycle pathway genes. Afterwards to evaluate the correlation between OSM and DNA synthesis and this role on metastasis, we evaluated the role of a novel anti-OSM therapeutic and its correlation with decreased metastasis. This research aims to elucidate the unique role OSM plays in ER+ and ER- breast cancer and will provide a molecular understanding of how this occurs and will provide detailed information on which patients will benefit most from anti-OSM therapeutics.
Citation Format: Cody L. Wolf, Ken Tawara, Cheryl L. Jorcyk. Understanding the differential role of an IL-6 family cytokine in varying subtypes of breast cancer patients for novel therapeutic intervention [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 1389.
Abstract 144: Sex bias in neuroblastoma: Worse outcomes for female patients are associated with dysregulation of DLK1 and H19
Authors: Raleigh Mariya , Patel Vishwa , Benhamou Lorraine R. , Shen Xin , Sheeter Dennis A. , Espinosa Erika C. , Badi Niharika Reddy , Calvert Chase , Bourne Garrett , Powers John T. 
Published: March 2024

Abstract
Neuroblastoma (NB) is a devastating neural crest-derived tumor primarily affects children under five. Forty percent of NB patients are classified as high-risk (HR), and less than half of them survive. HR disease is split into two equally sized groups: one exhibiting genetic amplification of the MYCN proto-oncogene (MA), and another where MYCN is non-amplified (MNon). Overall survival (OS) studies are often either poorly annotated or focused on outcomes across the entire patient group, which may mask differential outcomes or biases among NB subgroups. Here we report our assessment of OS among several genetic, histopathological, and sex-based subgroups in three different well annotated NB patient datasets. Our analysis reveals a previously unseen sex-bias in HR MNon patients, where female patients have significantly worse OS than males. This disparity carries into stage 4s NB, defined by high survival in infants despite the presence of broadly disseminated disease. In stage 4s patients across two studies, we observe no deaths among males (n=66) and 6 among females (n=48), again marking significantly worse OS in females. Expression analysis comparing male and female HR MNon patients identifies DLK1 and H19, two imprinted genes implicated in multiple malignancies, as frequently overexpressed in females. A similar pattern is seen in RNA seq analysis of human MA (n=4) and MNon (n=4) cell lines. In addition, both DLK1 and H19 are associated with worse prognosis in female but not male patients. We also report that depletion of either gene results in reduced growth in vitro. Moreover, the NB-related ATRX tumor suppressor has been shown to inhibit H19 via insertion of histone variant H3.3. We observe an inverse correlation between H3.3B and H19 expression in female HR MNon patients. Further, H19 levels increase upon ATRX depletion in human NB cells, suggesting that ATRX indeed regulates H19 in NB. These findings provide the first evidence of female-biased outcomes in NB and suggest functional involvement of DLK1, H19 and ATRX.
Citation Format: Mariya Raleigh, Vishwa Patel, Lorraine R. Benhamou, Xin Shen, Dennis A. Sheeter, Erika C. Espinosa, Niharika Reddy Badi, Chase Calvert, Garrett Bourne, John T. Powers. Sex bias in neuroblastoma: Worse outcomes for female patients are associated with dysregulation of DLK1 and H19 [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 144.