bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A036: Cell Avidity – The Next-Gen cell binding to understand the mechanism of action through cell-cell and cell-protein interaction
Authors: Mellen Russell W , Moser Justin 
Published: February 2025

Abstract
While conventional assays such as affinity, cytokine secretion, and cytotoxicity provide valuable data at a molecular level, this information is insufficient to fully characterize and select the best cellular therapies. There is still a lack of understanding about cell-cell interactions that drive functional processes. Methods: Cell avidity, the collective strength of interactions between an effector and its target, can help elucidate the mechanism of action for therapeutic candidates. Our highly flexible Cell Avidity platform, the z-Movi Cell Avidity Analyzer, combines fluorescence microscopy with acoustic force to distinguish cell binding in a physiological context. This provides a comprehensive view of cell binding characteristics to interrogate potency, safety, sensitivity, and binding kinetics. Results: Here, we review recent publications highlighting how researchers have used Cell Avidity to: •Format-tune in vivo-launched bispecific T cell engagers to enhance efficacy against renal cell carcinoma. •Venetoclax-treated NK cells to improve cytoskeleton remodeling and lytic granule polarization, contributed to a more efficient IS, enhancing NK cell-mediated killing of AML cells. •Engineer CAR-T cells secreting a T-cell engaging molecule to overcome a challenging tumor microenvironment in pancreatic adenocarcinoma. •Phenotype the tumor-primed NK cells for cell binding and function •Fine-tune the affinity/cell avidity of CAR-T cells to mitigate on-target off-tumor toxicity in renal cell carcinoma. Conclusions: Cell Avidity is an emerging biomarker that directly quantifies the strength of the physical interactions between target and effector cells. We developed a Cell Avidity platform that enables the characterization and screening of molecular binders and cellular products, including antibodies, small molecules, and cell therapies. Cell Avidity provides comprehensive information on potency, safety, sensitivity, and kinetics, offering key insights into the mechanism of action for cell therapies.
Citation Format: Russell W Mellen, Justin Moser. Cell Avidity – The Next-Gen cell binding to understand the mechanism of action through cell-cell and cell-protein interaction [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A036.
Abstract A041: Combined inhibition of S100A4 and TIGIT suppresses late-stage breast cancer metastasis to the lung by activating T and NK cells
Authors: Leu Jia-Shiun , Deng Hui , Xiong Wei , Tran Han Nhat , Hashimoto Chihiro , Leonard Fransisca , Wong Thomas , Abdelfattah Nourhan , An Zhiqiang , Zhang Ningyan , Yun Kyuson 
Published: February 2025

Abstract
Cancer metastasis is responsible for approximately 90% of cancer-related deaths but a very few treatment options exist currently. For decades, the role of S100A4 in promoting metastasis has been validated in multiple ways. More recently, our single cell RNA-sequencing analysis of human gliomas and other cancers showed that S100A4 is highly expressed in immune suppressive myeloid and T cells. Consistently, removing S100A4 from the host microenvironment suppresses tumor growth from injected MC38, BL16, or E0771 murine cancer cells, strongly supporting its pro-tumorigenic role in the TME and nominating it as a novel immunotherapy target. To translate these findings, we developed a novel antibody against the human S100A4 protein to block its function in the TME. The monoclonal antibody (mAb) S1004-11 effectively suppresses breast cancer metastasis in two different mouse models. Mechanistically, S1004-11 mAb treatment blocks the pre-metastatic niche formation in the lung by suppressing neutrophil infiltration, activating NK and T cells, and altering cell-to-cell communication among stromal and immune cells. Additionally, S100A4-11 treatment reduces circulating M-MDSCs and Tregs in the blood, and CD163+ but not CD206+ macrophages in the primary breast tumor. Notably, single cell RNA-seq and cell:cell communication analyses suggest that NK cells in the lung are suppressed by TIGIT signaling, suggesting that anti-TIGIT treatment may suppress lung metastases and synergize with S100A4 inhibition. To simulate clinical scenario where many breast cancer patients are diagnosed with existing micro or macro metastases, we tested whether S100A4-11 or anti-TIGIT antibody can suppress lung metastases when the treatment is initiated after the lung niche formation is complete. While S100A4-11 or anti-TIGIT treatment alone was not sufficient to suppress lung metastases at this late stage, the combined treatment of S100A4-11 and TIGIT significantly reduced lung nodule formation. Taken together, these results indicate that S100A4 can suppress breast cancer metastasis through different mechanisms at different stages of metastases progression, and nominates anti-S100A4+anti-TIGIT as a novel combination therapy to block late lung metastasis.
Citation Format: Jia-Shiun Leu, Hui Deng, Wei Xiong, Han Nhat Tran, Chihiro Hashimoto, Fransisca Leonard, Thomas Wong, Nourhan Abdelfattah, Zhiqiang An, Ningyan Zhang, Kyuson Yun. {Abstract title} [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A041.
Abstract A055: Dissecting mechanisms of tumor anti-PD1 resistance due to host genetic variation within ADAM17
Authors: Heiserman James P , Akhurst Rosemary , Desai Tanuja , Chen Sharon 
Published: February 2025

Abstract
Clinical application of anti-PD1 or anti-PDL1 antibodies, also known as Immune checkpoint blockade (ICB) therapy, has shown potential as an anti-cancer treatment. However, currently only 10 to 30 percent of cancer patients responds to ICB. Successful ICB treatment depends on a variety of factors including tumor mutation burden, cancer subtype, and patient genetics, the latter of which is currently understudied. Therefore, there is a clear need to understand how host genetics influences ICB clinical success to improve patient outcomes. Our laboratory primarily focuses on the study of transforming growth factor-beta (TGFβ) signaling across a variety of disease contexts. We have generated two congenic mouse strains that harbor either NIH or C57 genomic DNA at the proximal end of chromosome 12 NIH/Ola that differentially regulate TGFβ signaling. The C57 congenic region, include variant tumor necrosis-alpha converting enzyme (TACE, encoded by Adam17). Utilizing these congenic mice in syngeneic cancer models, we generated preliminary data suggesting that C57 “hypoactive” Adam17 variant (with two non-synonymous SNPs at D113N and I613V) correlates with better response to ICB compared to congenic mice that harbor NIH Adam17 allele, which are resistant to ICB therapy. Considering the discrepancy in both ICB response and ADAM17 activity, we employed a Wyeth developed highly specific small molecule inhibitor of TACE (TMI-2) in vivo and found it can resensitize ICB resistant mice to ICB treatment, suggesting that ADAM17 activity may suppress ICB efficacy. We have also performed initial immunotyping analysis on ICB these sensitive and resistant congenic mice, with and without ICB, and have found differences in myeloid and T cell infiltrate into the tumor microenvironment, suggesting that ADAM17 may regulate the tumor microenvironment landscape. We have preliminary in vitro data suggesting that hypoactive variants of T cell ADAM17 may reduce T cell death through inhibition of release of tumor necrosis factor alpha, which is known to induce T cell death via TNFR1. This study provides support for utilizing ADAM17 as a therapeutic target for patients who harbor ICB resistant cancers and provides potentially invaluable insights into the consequences of ADAM17 activity in T cell dependent tumor biology.
Citation Format: James P Heiserman, Rosemary Akhurst, Tanuja Desai, Sharon Chen. Dissecting mechanisms of tumor anti-PD1 resistance due to host genetic variation within ADAM17 [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A055.
Abstract A056: A novel dual drug antibody-drug conjugate targeting hTrop2 has synergetic anti-tumor activity by enhancing systemic immunity
Authors: Zhu Jie , Zhao Xiaobei , Luo Zhenwu , Li Eileen , Xu Hong , Wu Cindy , Chen Gang , Nie Lei , Wang Haibin 
Published: February 2025

Abstract
Cancer therapy faces numerous challenges that can limit the effectiveness of treatment. In order to address these key hurdles, such as immunosuppression, tumor heterogeneity, and the likelihood of resistance, and offer longer-lasting control of the tumor, we’ve developed a novel dual drug ADC (BiADC), BR113, by conjugating an anti-hTrop2 antibody with a drug linker of a Topoisomerase I inhibitor payload, and another drug linker of an immunostimulator payload. The approach combining the direct cytotoxic effects of ADCs with the immune-enhancing properties of an immunostimulator not only eradicates tumor cells but also reprograms the tumor microenvironment, leading to durable and systemic anti-cancer immunity. Our in vitro studies proves that each BiADC molecule exerts biological functions from two distinct payloads. It not only directly kills tumor cells by inducing apoptosis or other forms of cell death from the payload toxin, but also releases cytokines, and chemokines from an activated innate immune system to activate tumor killing cells, such as T cells and natural killer (NK) cells. In vivo models proves that the combination of two payloads increases the tumor infiltrated immune cells population and turns immunologically "cold" tumors into "hot" tumors, making them more susceptible to immune-mediated attack. In a syngeneic mouse model, BR113 exhibits great treatment efficacy and survival benefit with a prolonged anti-tumor protection against the tumor re-challenge. In a more aggressive B16F10 tumor model, this synergistic anti-tumor activity is further confirmed with the combination of BiADC and check point inhibitors, which further improved anti-tumor activity significantly and completely controled tumor growth. Overall, this new ADC/IO combination therapy maximizes the activity of each drug and reduces the toxicity of each individual payload. The dual anti-tumor MOAs exert a synergistic effect by enhancing systemic immunity, which ensures comprehensive and sustained tumor control, making it a powerful strategy for improving patient outcomes.
Citation Format: Jie Zhu, Xiaobei Zhao, Zhenwu Luo, Eileen Li, Hong Xu, Cindy Wu, Gang Chen, Lei Nie, Haibin Wang. A novel dual drug antibody-drug conjugate targeting hTrop2 has synergetic anti-tumor activity by enhancing systemic immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A056.
Abstract A058: nELISA high-throughput protein profiling captures immune secretomes for high-resolution phenotypic screens
Authors: Rosenbloom Alyssa , Robichaud Nathaniel , Ongo Grant , Dagher Milad 
Published: February 2025

Abstract
Immune phenotypes can be extremely diverse and complex, posing both a challenge to understand them and an opportunity to target them with advanced immune engineering approaches. Unfortunately, proteomics tools that capture the breadth of possible immune responses lack the throughput and affordability to rapidly profile the large sample numbers generated to identify and characterize optimally engineered therapeutic candidates. To overcome this issue, we developed the nELISA: a high-throughput miniaturized ELISA capable of quantifying &gt;275 cytokines, proteases, immune receptors, and growth factors, at 10x-reduced cost compared to previous tools. We applied the nELISA to a model high-throughput screen for the discovery and characterization of immune-modulatory perturbations. We ran the largest PBMC secretome screen to date, in which ∼10,000 PBMC samples were profiled in 1 week, at a throughput of 1536 samples/day. Cells were treated with various inflammatory stimuli, and were further perturbed with a selected library of 80 recombinant protein perturbagens. The broad nELISA content enabled us to capture disease phenotypes and donor variability, as well as distinguish between perturbations with similar effects on single markers but vastly different overall phenotypes. For example, IFN gamma was potently induced by &gt;12 perturbagens with very different effects on other cytokines. Thus, IL-23 had almost no impact other than to induce IFN gamma; in contrast, IL-15 also induced IL-1 beta, TNF alpha, CXCL9, CXCL10, and CCL5, whereas IFN beta impacted the expression of &gt;20 cytokines in addition to IFN gamma. Interestingly, we also identified perturbagens that could substitute for another, while avoiding deleterious effects. Thus, IL-1 Receptor antagonist shared all of the immunosuppressive effects of IFN beta, without inducing IFN gamma and CXCL10, supporting its use as a replacement for Type I interferons in certain indications such as multiple sclerosis. These findings highlight the ability of the nELISA to capture a wide range of immune phenotypes at a throughput and cost amenable to immune engineering studies.
Citation Format: Alyssa Rosenbloom, Nathaniel Robichaud, Grant Ongo, Milad Dagher. nELISA high-throughput protein profiling captures immune secretomes for high-resolution phenotypic screens [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A058.
Abstract A060: Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance
Authors: Moffat Jason 
Published: February 2025

Abstract
Glioblastoma (GBM) thrives in an ecosystem that is shaped by intricate intercellular interactions that contribute to tumor progression and treatment resistance. Recent studies have shown that the oligodendrocyte lineage (OL) is abundantly enriched in the GBM tumor microenvironment. In this study, we utilized single-cell RNA sequencing (scRNA-seq) profiles from 120 primary and recurrent GBM tumors, spatial transcriptomics, immunohistochemistry, cytokine profiling, and in vitro migration assays to demonstrate that OLs are selectively recruited to the GBM tumor border, and subsequently incorporated into the tumor mass at recurrence. Using a pan-disease single-cell human OL meta-atlas, we identified a population of malignancy-associated reactive OLs, akin to those seen in demyelinating inflammatory and traumatic conditions. The interferon-mediated induction of this population was validated using in vivo GL261 and CT2A syngeneic mouse models. Cytokine profiling and ligand-receptor (LR) interaction analyses identified several pro-tumorigenic cytokines secreted by reactive OLs, including CCL5. Moreover, we found that CCR5, the CCL5 receptor, was preferentially expressed in glioma stem-like cells (GSCs) and upregulated at recurrence. Targeting CCR5 in GBM tumor cells with genetic knockdown or pharmacological inhibition impaired GSC stemness and prolonged the survival of mice bearing GBM tumors. Our work highlights the functional interplay between OLs and GBM cells and positions the CCL5/CCR5 axis as a druggable target for GBM.
Citation Format: Jason Moffat. Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A060.
Abstract A063: Inhibition of TREX1 increases type I interferon signaling and reduces tumor growth in vivo
Authors: Singh Madhurendra , Silvander Camilla , Livendahl Madeleine , Bansal Ritu , Gripenberg Anton , Trésaugues Lionel , Ubhayasekera Wimal , Romero Adrian , Ye Weihua , Lindstrom Johan , Moussaud Simon , De Milito Angelo , Andersson Martin 
Published: February 2025

Abstract
TREX1 exonuclease prevents cytosolic DNA-driven cell-intrinsic IFN response and subsequent inflammation and immune activation. Indeed, TREX1 induction in cancer cells has been shown to inhibit the IFN response and dampen antitumor immunity, suggesting TREX1 as a promising target for cancer therapy. Sprint Bioscience develops small-molecule drugs by using a fragment- and structure-based approach. Diverse projects focused on oncology, including TREX1, are developed in parallel using Sprint Bioscience's multidisciplinary drug development platform. We have developed small-molecule TREX1 inhibitors (TREX1i) with sub-nanomolar biochemical potency and high selectivity. Using a reporter cell line to monitor IRF activation, we show low nanomolar cellular potency of the inhibitors. We also demonstrate that in the colon cancer HCT116 cells, our leading TREX1i induces innate immune signaling pathways at protein levels such as phospho-TBK1 and STAT1. Moreover, in the CT26 syngeneic mouse model, the front-runner TREX1i significantly reduces tumor growth and increases immune cell infiltration measured by flow cytometry. Unbiased Nanostring IO 360 panel analysis performed in vehicle and TREX1i-treated CT26 tumors showed that pharmacological TREX1 inhibition is associated with the induction of multiple IFN-stimulated genes (ISGs), antigen processing & presentation machinery (APP) genes (such as TAP1, B2M, and HLA genes), and STING-TBK1-IRF3-induced chemokines (such as CCL5 & CXCL-10). In conclusion, our data using pharmacological TREX1 inhibition support recent publications reporting the anti-tumor immunity effects linked to genetic TREX1 inhibition in vivo and indicate that TREX1i have promising potential for use as a therapeutic intervention in oncology.
Citation Format: Madhurendra Singh, Camilla Silvander, Madeleine Livendahl, Ritu Bansal, Anton Gripenberg, Lionel Trésaugues, Wimal Ubhayasekera, Adrian Romero, Weihua Ye, Johan Lindstrom, Simon Moussaud, Angelo De Milito, Martin Andersson. Inhibition of TREX1 increases type I interferon signaling and reduces tumor growth in vivo [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A063.
Abstract A068: HDAC1 and HDAC3 inhibition decreases myeloid derived suppressor cell function through STAT3-mediated apoptosis
Authors: Baugh Aaron G. , Gonzalez Edgar , Zhong Sabrina K. , Jacobo Matthew B. , Acevedo Kaliya , Kreger Jesse , Liu Yingtong , MacLean Adam L. , Roussos Torres Evanthia T. 
Published: February 2025

Abstract
Myeloid derived suppressor cells (MDSCs) are key players in an immune-suppressed tumor microenvironment (TME) and significantly contribute to immune checkpoint inhibition (ICI) resistance, making them favorable targets for cancer immunotherapy. Our group and others have investigated MDSCs as a therapeutic targets to sensitize the TME to ICIs in breast cancer. We have reported that epigenetic reprogramming of MDSCs by inhibiting histone deacetylases (HDACs) 1 and 3 with Entinostat decreases MDSC immunosuppressive function and contributes to ICI response. However, a clear molecular mechanism of HDAC1/3 inhibition driving ICI response has yet to be understood. In breast intratumoral MDSCs, breast-to-lung metastatic MDSCs, and an MDSC-like cell line, we found that Entinostat decreases phosphorylation and activation of STAT3, a transcription factor shown to play a role in MDSC suppression of T cells. We hypothesized that Entinostat decreases MDSC suppression through modulation of the STAT3 pathway. Chromatin immunoprecipitation sequencing (ChIP-seq) of J774M, an MDSC-like cell line, treated with Entinostat revealed differential promoter binding by STAT3. KEGG pathways analyses of STAT3-bound promoters revealed significant enrichment of the Apoptosis pathway, of which Entinostat decreased STAT3 enrichment at the promoter of Mcl1, a protein in the Bcl2 family that normally prevents apoptosis and promotes survival in MDSCs. We also found that treatment of J774M cells with STAT3 inhibitors C188-9 and Stattic decreased cell proliferation and increased cell death. Our findings provide new evidence implicating a STAT3-mediated mechanism leading to decreased MDSC suppressive signaling and function upon HDAC 1/3 inhibition. These findings and planned studies may lead to a more complete understanding of the mechanism driving response in the combination therapy of Entinostat + ICIs, potentially informing development of more specific therapeutics for future preclinical studies and identification of biomarkers for clinical screening.
Citation Format: Aaron G. Baugh, Edgar Gonzalez, Sabrina K. Zhong, Matthew B. Jacobo, Kaliya Acevedo, Jesse Kreger, Yingtong Liu, Adam L. MacLean, Evanthia T. Roussos Torres. HDAC1 and HDAC3 inhibition decreases myeloid derived suppressor cell function through STAT3-mediated apoptosis [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A068.
Abstract A078: Platelet factor 4 (PF4)-dependent suppression of anti-tumor immunity by Th1-Treg polarization can be a novel immunotherapeutic target
Authors: Yamamoto Masahiro , Kuratani Ayumi 
Published: February 2025

Abstract
The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs) that strongly inhibit anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in the TME. Here we have created a mouse line, in which tumor associated macrophages (TAMs) can be selectively depleted using VeDTR mouse system. Suprisingly, we found that selective depletion of arginase I-expressing TAMs (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the ratio of Th1-Treg cells in the TME. Arg1+ TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-γ (IFN-γ)-induced Treg polarization into Th1-Tregs. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in the TME to suppress anti-tumor immunity, and demonstrates that its intervension can be a novel oncoimmunotherapeutic measure.
Citation Format: Masahiro Yamamoto, Ayumi Kuratani. Platelet factor 4 (PF4)-dependent suppression of anti-tumor immunity by Th1-Treg polarization can be a novel immunotherapeutic target [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A078.