tbuckley/cabot-search huggingface dataset:
Abstract 6564: Conversion of fibroblasts into Cancer-associated-fibroblasts (CAF) by small extracellular vesicles from EGFR mutated adenocarcinoma: Implication of SDC1 in the establishment of the lung premetastatic niche
Authors: Amina Jouida, Cormac McCarthy, Michael P. Keane
Journal: Cancer Research (2025)

Abstract Evidence across several cancer types supports the existence of metastasis-supportive microenvironments, called the premetastatic niche (PMN) which form at sites of future metastasis, allowing the colonization and growth of disseminated tumour cells. Extracellular vesicles (EVs) contribute to the establishment of a favourable microenvironment by the development of those niches. EVs and their contents have emerged as a potential source of information on tumour detection and regulatory drivers of tumour progression and metastasis. Recently, we have demonstrated that EVs are mediators of EMT and tumour invasion. We reported that EVs derived from serum of patients with EGFR mutated non-small cell lung cancer (NSCLC) mediates the activation of the PI3K/AKT/mTOR pathway and induce an invasion in epithelial cells through the up-regulation of MMP-9 by promoting partial EMT. This study aims to investigate the impact of EVs on fibroblasts, another key component of the PMN. Using PCR, we observed increased expression of fibroblast activation protein (FAP), COL1a1, MMP-2, and fibronectin in human lung fibroblasts treated with EVs derived from the EGFR-mutated cell line HCC827. Functional assays revealed that these EV-treated fibroblasts exhibited enhanced invasive and migratory abilities, as shown through a modified Boyden chamber assay and a wound healing assay. We also showed that the knock-out of SDC-1 prevents the activation of fibroblast by sEVs. Additionally, in an indirect co-culture system, epithelial cells exposed to EVs were capable of activating and recruiting fibroblasts. Our results suggest that EVs derived from EGFR-mutated adenocarcinoma serum could be a potential contributor to the establishment of a favourable metastatic microenvironment through the remodelling of the stroma. This may provide insights into the mechanisms of lung cancer progression and metastasis. However, additional studies are required to precisely delineate these mechanisms. Citation Format: Amina Jouida, Cormac McCarthy, Michael P. Keane. Conversion of fibroblasts into Cancer-associated-fibroblasts (CAF) by small extracellular vesicles from EGFR mutated adenocarcinoma: Implication of SDC1 in the establishment of the lung premetastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6564.
Abstract 2180: Utilization of multiparameter flow cytometry for immune monitoring of tumor infiltrating lymphocytes isolated from fresh tumor tissue
Authors: Rachel Owen, Angelina Bisconte, Deborah Phippard
Journal: Cancer Research (2025)

Abstract A multiparameter flow cytometry panel was designed to assess immune populations infiltrating solid tumors. Obtaining viable immune cells from fresh tissue for analysis can be challenging, however, using optimized shipping conditions and isolation procedures developed by Precision for Medicine (PfM) for fresh solid tumor biopsy pieces or fine needle aspirates, a variety of solid tumor indications, including melanoma, colorectal adenocarcinoma, sarcoma, triple negative breast cancer, renal cancer, head &amp; neck cancer, lung cancer and stomach cancer, were analyzed by flow cytometry. Following overnight shipment from collection sites to PfM’s laboratory, a real time sample processing procedure using a mechanical dissociation protocol followed by multiparametric flow cytometric analysis was performed. Post dissociation of tumor samples, cell viabilities ranged between 50-90%, and the sample quality was sufficient for flow cytometric analysis of tumor infiltrating lymphocytes (TILs). This analysis revealed that the frequency and phenotype of infiltrating immune cells could be assessed successfully. It was observed that variations in the frequency and phenotype of infiltrating cells were present in the tumor tissues. This study shows that real time multiparametric flow cytometric analysis of fresh tumor tissues, within 48 hours of collection, can be implemented in clinical trials with careful planning and consideration of clinical operations. This is of value for early phase clinical studies evaluating the impact of immune therapies on immune cell infiltration within solid tumors, and provides an additional immune monitoring tool. Citation Format: Rachel Owen, Angelina Bisconte, Deborah Phippard. Utilization of multiparameter flow cytometry for immune monitoring of tumor infiltrating lymphocytes isolated from fresh tumor tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2180.
Abstract 5089: Cross-platform comparison of snRNAseq, Visium, and Xenium on lung and breast cancer samples
Authors: Mariia Bilous, Daria Buszta, Jonathan Bac, Yixing Dong, Sylvie André, Marina Alexandre-Gaveta, Senbai Kang, Krisztian Homicsko, Raphael Gottardo
Journal: Cancer Research (2025)

Abstract Background: Spatial transcriptomics is revolutionizing biology and pathology of cancer by enabling the spatial analysis of RNA profiles in formalin-fixed tissues. However, the comparative performance of different platforms and their potential complementarity remain unclear. Methods: We conducted a comprehensive analysis of single-nuclei RNA sequencing (snRNAseq, n=15), full-transcriptome Visium v2 (n=10), and Xenium (n=40) on lung and breast cancer samples. This allowed a direct comparison between Visium and Xenium and an assessment of how snRNAseq can complement these spatial platforms. Results: Our findings highlight that Xenium provides high-resolution spatial data with single-cell accuracy and robust performance on FFPE tissues. We demonstrate that snRNAseq enhances Xenium analysis by facilitating automated cell annotation, quality control, and imputing missing gene expression profiles. Although Visium’s full transcriptome capabilities offer broader coverage, its resolution is limited and remains a challenge for interpretation, even when refined with super-resolution modeling (e.g., BayesSpace). Conclusion: Xenium excels in resolution and single-cell spatial mapping, seamlessly integrating with snRNAseq without requiring additional normalization. While Visium offers full transcriptome data, its resolution restricts biological interpretation. Together, Xenium and snRNAseq provide a powerful framework for spatial transcriptomics, advancing insights into tissue biology and pathology. Citation Format: Mariia Bilous, Daria Buszta, Jonathan Bac, Yixing Dong, Sylvie André, Marina Alexandre-Gaveta, Senbai Kang, Krisztian Homicsko, Raphael Gottardo. Cross-platform comparison of snRNAseq, Visium, and Xenium on lung and breast cancer samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5089.
Abstract 5840: PF-08046037, a PD-L1 targeted TLR7 agonist ISAC, drives innate immune activation and anti-tumor efficacy in preclinical in vitro and in vivo models
Authors: Giacomo Tampella, Catalina Sakai, Weiping Zeng, Eleanor Hendrickson, Sasha Lucas, Kung-Pern Wang, Aly Smith, Ryan A. Heiser
Journal: Cancer Research (2025)

Abstract PF-08046037 (formerly known as SGN-PDL1iT) is an immune-stimulating antibody conjugate (ISAC) designed to induce an immune response against cancer cells by delivering a potent Toll-like receptor 7 (TLR7) agonist to tumor associated antigen-presenting cells (APCs) expressing PD-L1. The ISAC consists of an anti-PD-L1 antibody linked to an imidazoquinoline-based TLR7 agonist using a mannosidase-cleavable maleimidopropionyl-mannose linker (mp-mann). Upon binding to PD-L1 on APCs, PF-08046037 internalizes and releases the payload into TLR7-containing endosomes. To minimize off-target immune activation, PF-08046037 incorporates Fc mutations in the antibody to reduce FcγR binding, and the agonist payload is designed to have low membrane permeability. Through targeting PD-L1-expressing immunosuppressive macrophages and dendritic cells within the tumor and associated immune compartments, PF-08046037 aims to repolarize the suppressive tumor microenvironment, enhance antigen presentation, and establish robust anti-tumor immunity. Here, we present preclinical data demonstrating the potency, targeted delivery, and anti-tumor efficacy of PF-08046037 in both in vitro and in vivo models. In vitro, PF-08046037 induces potent and selective activation of TLR7 reporter cells and PD-L1-expressing human macrophages and dendritic cells. In syngeneic hPD-L-1 .CT26 and hPD-L-1 .MC38 tumor models using human PD-L1-expressing mice, PF-08046037 shows single-agent efficacy and provides anamnestic protection against tumor rechallenge. The in vivo pharmacodynamic effects of PF-08046037 align with its intended mechanism of action, including acute tumor inflammation, loss of CD206+ suppressive macrophages, upregulation of activation and costimulatory molecules on APCs in tumors and tumor-draining lymph nodes (tdLN), and increased activity of cytotoxic cells. Collectively, these data highlight the therapeutic potential of targeted TLR7 agonist delivery to PD-L1-expressing APCs in cancer and support the clinical investigation of PF-08046037 in advanced malignancies. Citation Format: Giacomo Tampella, Catalina Sakai, Weiping Zeng, Eleanor Hendrickson, Sasha Lucas, Kung-Pern Wang, Aly Smith, Ryan A. Heiser. PF-08046037, a PD-L1 targeted TLR7 agonist ISAC, drives innate immune activation and anti-tumor efficacy in preclinical in vitro and in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5840.
Abstract 5111: Targeting the dysadherin/CA9 axis inhibits colorectal cancer adaptation and growth within the acidic tumor microenvironment
Authors: Jeong-Seok Nam, Choong-Jae Lee, Hyeon-Ji Yun
Journal: Cancer Research (2025)

Abstract The tumor microenvironment (TME) has a significant impact on colorectal cancer (CRC) progression by promoting tumor survival and aggressive behavior. A key player in this process is the tumor-associated glycoprotein dysadherin, which is highly expressed in aggressive CRC cells and facilitates their adaptation to the TME. In this study, we conducted a comprehensive bioinformatics analysis of clinical genomic data from CRC patients, integrated with studies on dysadherin-knockout CRC cells. We also examined the downstream effects of dysadherin in human CRC cells, patient tissue samples, and a xenograft mouse model. Through bioinformatics and pathological analysis, we found that increased tumor acidity is a prominent feature of CRC progression and is positively associated with high dysadherin expression. Overexpression and silencing studies of dysadherin in CRC cells further confirmed that high dysadherin levels enhance malignant traits, especially under acidic conditions within the TME. Mechanistically, dysadherin activates the Integrin/FAK/STAT3 signaling pathway, leading to upregulation of carbonic anhydrase 9 (CA9). CA9 helps cancer cells survive in acidic environments by maintaining intracellular pH balance. By buffering the acidic TME, CA9 enhances CRC cell adaptation and resilience in an otherwise hostile environment. Notably, the deletion of dysadherin in xenograft models led to reduced tumor growth, while the reintroduction of CA9 restored malignancy, underscoring the essential role of the dysadherin/CA9 axis. This pathway is crucial for CRC cell survival in acidic TME, positioning dysadherin and CA9 as promising prognostic markers and therapeutic targets. Targeting this axis could disrupt CRC progression, offering new therapeutic avenues and potentially more effective interventions for inhibiting disease advancement Citation Format: Jeong-Seok Nam, Choong-Jae Lee, Hyeon-Ji Yun. Targeting the dysadherin/CA9 axis inhibits colorectal cancer adaptation and growth within the acidic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5111.
Abstract 5900: Tumor-independent cfDNA methylation analysis for cancer monitoring during total neoadjuvant treatment in rectal cancer patients
Authors: Kim Nguyen-Ta, Grace Zhao, Heng Wang, Teressa Celma, Lisa Kim, Jeff Pawelek, Bram Herman, Annie Wu, Yun Bao, Gregory Botta, Aaron Miller, Hitendra Patel, Shengrong Lin, Peter Vu
Journal: Cancer Research (2025)

Abstract Introduction: Total neoadjuvant therapy (TNT) is the standard curative-intent treatment for locally advanced rectal cancer (LARC), where patients receive all of their chemotherapy and radiation therapy before surgery. However, monitoring treatment response during TNT can be challenging since radiographic changes are often delayed. Methylation changes in colorectal cancer (CRC) and other cancers are relatively consistent and can be monitored in real time using cell-free DNA (cfDNA), making them a promising strategy for cancer detection and treatment monitoring. This study aims to determine if methylation changes in cfDNA can be used to monitor treatment response in LARC undergoing TNT. Methods: Plasma of CRC patients stage I-IV and healthy controls were obtained to establish the methylation classifier. Patients with stage II or III rectal cancer undergoing TNT were recruited. Blood samples were collected at baseline and about 6 weeks after the start of treatment. Tumor and normal CRC genomic DNA were analyzed using the Agilent Avida Methyl 3400 DMR panel to generate a methylation index score. Cancer treatment response was assessed by the investigator based on computed tomography and/or magnetic resonance imaging. Results: We confirmed low background methylation signals in cfDNA and peripheral blood mononuclear cells of healthy controls. Subsequently, we analyzed methylation signals from plasma of CRC patients with stage I (n=20), II (n=12), and IV (n=5) disease. The sensitivity of the assay was 60%, 75%, and 100% for stages I, II, and IV, respectively, while the specificity was 87.5%. Among LARC patients undergoing treatment with TNT, we observed a decrease in methylation index scores compared to baseline in all three patients who experienced a treatment response and an increase in all three patients who experienced disease progression. Notably, the methylation index scores did not correlate with carcinoembryonic antigen values. Conclusions: Our preliminary results show the feasibility of monitoring rectal cancer treatment response during TNT using a tumor-independent cfDNA methylation analysis. Methylation analysis is a promising technology that may aid in quantifying treatment response to systemic therapy and/or radiation. Citation Format: Kim Nguyen-Ta, Grace Zhao, Heng Wang, Teressa Celma, Lisa Kim, Jeff Pawelek, Bram Herman, Annie Wu, Yun Bao, Gregory Botta, Aaron Miller, Hitendra Patel, Shengrong Lin, Peter Vu. Tumor-independent cfDNA methylation analysis for cancer monitoring during total neoadjuvant treatment in rectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5900.
Abstract 7291: Advancing cancer immunotherapy: characterizing and leveraging bispecific antibodies targeting immune checkpoints
Authors: Jun Wang, Denise Garvin, Jonathan Mitchell, Pete Stecha, Michael Beck, Jim Hartnett, Kai Hillman, Gopal Krishnan, Frank Fan, Julia Gilden, Mei Cong, Jamison Grailer
Journal: Cancer Research (2025)

Abstract Bispecific antibodies targeting immune checkpoints are transforming cancer immunotherapy by enabling novel mechanisms of action unattainable by monospecific antibodies. These engineered molecules simultaneously engage two distinct epitopes, such as PD-1 and CTLA-4 or TIGIT, to amplify anti-tumor immune responses while minimizing off-target effects. Here we demonstrate the use of cell-based reporter bioassays to provide a robust platform for assessing the functional potency, stability, and specificity of bispecific antibodies. Combination bioassays, such as PD-1 + TIGIT and PD-1 + LAG-3, evaluate synergistic effects on T-cell activation. Additionally, Fc effector function bioassays, including ADCC and ADCP assays, assess the cytotoxic potential and receptor-mediated activity of bispecific formats. These assays ensure precise characterization of mechanisms of action, guiding the refinement of antibody designs. Citation Format: Jun Wang, Denise Garvin, Jonathan Mitchell, Pete Stecha, Michael Beck, Jim Hartnett, Kai Hillman, Gopal Krishnan, Frank Fan, Julia Gilden, Mei Cong, Jamison Grailer. Advancing cancer immunotherapy: characterizing and leveraging bispecific antibodies targeting immune checkpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7291.
Abstract 7288: Targeted degradation of mobile immune checkpoints to advance cancer therapy
Authors: Chao Wang, Yingqin Hou, Jaroslav Zak, Kelli A. McCord, Qinheng Zheng, Shereen Chung, Ruben D. Peraza, James C. Paulson, John R. Teijaro, Xu Zhou, K Barry Sharpless, Je!rey V. Ravetch, Matthew S. Macauley, Peng Wu
Journal: Cancer Research (2025)

Abstract Immune checkpoint inhibitors (ICIs) targeting T cell-intrinsic checkpoints, such as CTLA-4 and PD-1, have shown promising outcomes across diverse cancer patient populations. However, resistance to these ICIs remains prevalent, especially in patients with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. To overcome therapeutic resistance, there is an unmet need to identify novel immune checkpoints involved in cancer progression and to develop innovative therapeutic strategies capable of reprogramming the TME by neutralizing tumor-promoting factors. Here, we identify sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 as mobile immune checkpoints acquired by T cells from myeloid cells via trogocytosis in the TME. These trogocytosed Siglec checkpoints suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling pathways through engagement with tumor-associated sialoglycans. To target these mobile checkpoints, we leveraged sulfur(VI) fluoride exchange (SuFEx) click chemistry to develop a high-affinity Siglec-7/-9 ligand and converted it into a degrader for lysosomal degradation of both Siglecs. This degrader efficiently reduced Siglec levels in T cells and myeloid cells, significantly restoring T cell function and enhancing anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, remodeled the TME and generated durable T cell memory, resulting in excellent tumor control in multiple murine models. These findings underscore the significance of degrading exogenously acquired Siglec checkpoints on T cells as a novel strategy to overcome resistance to established ICIs in cancer therapy. Citation Format: Chao Wang, Yingqin Hou, Jaroslav Zak, Kelli A. McCord, Qinheng Zheng, Shereen Chung, Ruben D. Peraza, James C. Paulson, John R. Teijaro, Xu Zhou, K Barry Sharpless, Je!rey V. Ravetch, Matthew S. Macauley, Peng Wu. Targeted degradation of mobile immune checkpoints to advance cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7288.
Abstract 2037: Early identification of long-term survivors on tremelimumab plus durvalumab and chemotherapy in POSEIDON from pre-treatment CT images
Authors: Kedar Patwardhan, Harish RaviPrakash, Qin Li, Ross Stewart
Journal: Cancer Research (2025)

Abstract Background: The combination of CTLA-4 and PD-(L)1 inhibitors either with or without chemotherapy is an approved treatment for metastatic non-small-cell lung cancer (mNSCLC). Identifying which patients are most likely to derive additional benefit from these regimens, as compared anti-PD-1 alone or in combination with chemotherapy (CTx) would help optimize clinical management of these patients. Methods: Pre-treatment baseline Computed Tomography (CT) images of the thorax from patients treated with durvalumab plus tremelimulab (D+T; n=647) as part of the MYSTIC and NEPTUNE studies were split into a training (n=557) and a validation cohort (n=90). A 3D Deep Learning model with a DenseNet architecture was trained to predict patients with overall survival (OS) longer or shorter than the median (∼1 year), and then optimized using the validation set. The final model (named RaDx) was then applied de-novo to the non-squamous mNSCLC cohort from POSEIDON. Results: All reported hazard ratios (HR) are comparing RaDx+ and RaDx- groups unless specified otherwise. In the validation cohort, the median OS (mOS) in the RaDx+ (n=38) and the RaDx- (n=52) groups was 21 and 6.3 months respectively with HR=0.44 (0.27-0.73). In the anti-CTLA-4 containing arm of POSEIDON (D+T+CTx; n=187), the mOS for RaDx+ (n=77) and RaDx- (n=110) groups was 26.6 and 10.8 months respectively with HR = 0.44 (0.3-0.64). In the durvalumab and chemotherapy arm (D+CTx; n=182), the mOS for the RaDx+ (n=71) and RaDx- (n=111) groups was 17.2 and 11.2 months respectively with HR = 0.68 (0.48-0.97). In the CTx only arm (n=178), the mOS for the RaDx+ (n=73) and RaDx- (n=105) groups was 15.1 and 11.6 months respectively with HR = 0.82 (0.59-1.13). Within the RaDx+ sub-group a comparison of D+T+CTx to D+CTx patients favoured D+T+CTx with HR = 0.63 (0.42-0.96). Conclusions: We demonstrated feasibility that a Deep Learning model using baseline CT images may be used to identify a sub-group of patients for whom the addition of tremelimumab to chemo-immunotherapy may bring additional benefit. Such a biomarker could have the potential to guide optimal treatment selection in this 1L mNSCLC population. Citation Format: Kedar Patwardhan, Harish RaviPrakash, Qin Li, Ross Stewart. Early identification of long-term survivors on tremelimumab plus durvalumab and chemotherapy in POSEIDON from pre-treatment CT images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2037.