tbuckley/cabot-search huggingface dataset:
Abstract 5859: Circulating myeloid-derived suppressor cells (MDSC) are increased and correlated with immunosuppression, systemic inflammation and malnutrition in patients with anaplastic thyroid cancer
Authors: Masahiko Shibata, Shinichi Suzuki, Koji Kono, Seiichi Takenoshita
Journal: Cancer Research (2025)

Abstract Anaplastic thyroid cancer (ATC) is one of the most aggressive neoplasm in humans. Myeloid-derived suppressor cells (MDSC) contribute to the negative regulation of immune responses in cancer and are reported to be further increased in patients who immune checkpoint inhibitor is not effective. In order to investigate the pathophysiology of thyroid cancer, peripheral blood mononuclear cells (PBMC) were obtained from 49 patients with thyroid cancer, 18 with non-cancerous thyroid diseases and 22 healthy volunteers. MDSC were detected by flow cytometry (CD14-CD11b+CD33+) and Tcell-mediated immune response is measured by stimulation index (SI) of PHA-stimulated proliferation of lymphocytes. CRP (C-reactive protein) levels were used as inflammatory and serum albumin levels were used as nutritional parameters. MDSC levels were significantly higher in thyroid cancer than in healthy volunteers and non-cancerous patients, and those of ATC was highest among patients with thyroid cancer. SI were significantly lower, and CRP levels were higher in ATC than other histological types of thyroid cancer. The patients with thyroid cancer were divided into 2 groups with the average level of MDSC (1.578 %PBMC) in patients with thyroid cancer. CRP levels were significantly higher, serum albumin levels were significantly lower in high MDSC group than in low MDSC group. These data indicate that MDSCs are increased in patients with ATC. Furthermore, these patients exhibited immunosuppression, enhanced chronic inflammation and nutritional impairment. Citation Format: Masahiko Shibata, Shinichi Suzuki, Koji Kono, Seiichi Takenoshita. Circulating myeloid-derived suppressor cells (MDSC) are increased and correlated with immunosuppression, systemic inflammation and malnutrition in patients with anaplastic thyroid cancer [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 5859.
Abstract 2166: PTPN1/2 dual inhibition sensitizes solid tumors to checkpoint blockade immunotherapy by enhancing T cell cytotoxicity and by decreasing cancer cell immune evasion
Authors: Alexandre Poirier, Luis-Alberto Perez-Quintero, Erika Walback, Rui Su, Chenyue Wu, Michel L. Tremblay
Journal: Cancer Research (2025)

Abstract Immunotherapy has revolutionized the way we treat patients suffering from cancer. However, many patients are still refractory to immunotherapy, which highlights the importance of identifying new genetic targets that can achieve therapeutic outcomes. Recent work has revealed that protein tyrosine phosphatase non-receptor 2 (PTPN2) can act as such a target by enhancing T-cell and interferon responses against cancer. Development of PTPN2 inhibitors paves the way for a new therapeutic modality to fight solid malignancies. However, current inhibitors also inhibit PTPN1, a closely related phosphatase with largely different biological roles. There remains limited evidence, however, whether dual inhibitors are truly optimal in terms of efficacy, safety and biological activity, or whether PTPN2 specific inhibitors should be pursued. Our aim was thus to systematically investigate the role of these two phosphatases in T-cell responses and tumor immune escape, to further refine the use of PTPN1/2 inhibitors as a therapeutic modality against cancer. We found that in CD8+ T cells, PTPN2 is the major player in limiting cytotoxic activity against cancer cells. However, PTPN2 deletion alone shows only a modest increase in cytotoxicity and is accompanied by a compensatory enhancement of PTPN1 protein levels. Additional deletion of PTPN1 in PTPN2 deficient T cells (dKO) is required for maximal cytotoxic activity and for the establishment of a distinct T cell memory subcluster capable of resisting canonical exhaustion. On the tumor side, the deletion of both phosphatases results in the synergistic augmentation of CXCL9, a potent CD8+ T cell chemoattractant. Using various cancer models, we demonstrate that cancers insensitive to checkpoint blockade are made vulnerable to immunotherapy by PTPN1/2 inhibition. Dual PTPN1/2 inhibitors achieve this effect through distinct cancer cell and T cell-specific effects that act in a complementary manner to checkpoint blockade. We are now pursuing the development of our lead PTPN1/2 inhibitor in clinical trials for the treatment of solid malignancies. Citation Format: Alexandre Poirier, Luis-Alberto Perez-Quintero, Erika Walback, Rui Su, Chenyue Wu, Michel L. Tremblay.. PTPN1/2 dual inhibition sensitizes solid tumors to checkpoint blockade immunotherapy by enhancing T cell cytotoxicity and by decreasing cancer cell immune evasion. [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 2166.
Abstract 5857: Targeting KDELR2 remodels the immune tumor microenvironment for enhanced anti-cancer response
Authors: Shakti Prasad Pattanayak, Boaz Tirosh
Journal: Cancer Research (2025)

Abstract Inflammation within the tumor microenvironment (TME) boosts anti-cancer immune responses by activating both innate and adaptive immunity. In situ inflammation enhances antigen presentation, immune cell infiltration and supports immune-cancer cycle. KDEL receptors (R1, R2 &amp; R3) are critical for retaining KDEL proteins in the endoplasmic reticulum (ER). Their compromise can cause a concerted release of pro-immunogenic molecule, such as calreticulin. This can provoke conditions similar to immunogenic cell death (ICD) in the absence of chemotherapy. To address the role of KDEL receptors in immune-cancer interactions, we generated a mouse colon cancer model equipped with doxycycline (DOX)-induced silencing of the KDELRs. We found that in these cells KDEL-R2 isoform controls the intracellular retention of a large number of secretory proteins including calreticulin. Surprisingly, in vivo when cells with silenced KDEL-R2 were mixed with normal tumor cells in a 1:10 ratio and treated with DOX, tumors significantly regressed in mice. Analysis of the TME (via flow cytometry, IHC, and IF) revealed a massive infiltration of neutrophils and macrophages, most are polarized to M1. In vitro macrophage polarization studies confirmed that from the silencing of KDEL-R2 confers polarization. Using a novel biotin-labeled probe to detect extracellular PDIs, we confirmed the robust ICD intensity of KDEL proteins in the TME. In athymic Nu/Nu mice, KDEL-R2 silencing also induced tumor regression, underscoring the dominant role of innate immunity. Re-challenge experiments demonstrated T-cell priming and the establishment of immune memory, supported by T-cell and macrophage infiltration in the TME. Additionally, using tumor cells that present an antigenic MHC class I peptide, we demonstrate T cell priming in the absence of vaccination. This study reveals a significant advancement in cancer immunotherapy and potential for synergistic effect with other treatments such as CAR-T therapy and checkpoint inhibitors through immune memory and inflammation-driven immunity. Citation Format: Shakti Prasad Pattanayak, Boaz Tirosh. Targeting KDELR2 remodels the immune tumor microenvironment for enhanced anti-cancer response [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 5857.
Abstract 3969: Quantitative spatiotemporal analysis of patient-derived organoid-based tumor-immune microenvironment model in lung cancer for immunotherapy response prediction
Authors: Mahn Jae Lee, Joo-Eun Lee, Dahye Lee, Duk Ki Kim, Da Hyun Kang, Chaeuk Chung
Journal: Cancer Research (2025)

Abstract The tumor-immune microenvironment (TiME) plays a crucial role in cancer progression and treatment response, yet establishing physiologically relevant ex vivo models that accurately recapitulate TiME remains challenging. Here, we present a novel multi-modal analytical platform using lung cancer patient-derived organoids (PDOs) and autologous lymphocytes to model TiME, aiming to predict immunotherapy responses and guide treatment strategies. We developed an integrated analytical platform combining: (1) PDO-lymphocyte co-culture system using autologous cells isolated from lung cancer patients, (2) multiplexed immunofluorescence imaging for spatial analysis of immune cell distribution, (3) label-free holotomography for real-time visualization of TiME dynamics, and (4) comprehensive genomic profiling. The formation and architecture of TiME were validated through quantitative spatiotemporal immunophenotyping. Machine learning algorithms were employed to integrate multi-modal data and identify predictive signatures for treatment responses. Our integrated platform successfully reconstituted patient-specific TiME models that maintained key molecular and cellular characteristics of original tumors. Real-time holotomographic imaging revealed distinct patterns of immune cell migration and tumor-immune cell interactions. Quantitative spatiotemporal analysis demonstrated specific immune response signatures correlating with clinical outcomes. Integration of multi-modal data through machine learning algorithms showed significant predictive value for immunotherapy responses. The platform successfully identified differential drug responses in patient-specific models, correlating with clinical treatment outcomes. We established a novel multi-modal analytical platform for studying tumor-immune interactions in patient-specific models. The integration of spatial, temporal, and molecular analyses provides comprehensive insights into TiME dynamics and treatment responses. This platform shows promise as a predictive tool for immunotherapy outcomes and could serve as a personalized drug screening system, presenting new opportunities for patient stratification and therapeutic strategy optimization in lung cancer treatment. Citation Format: Mahn Jae Lee, Joo-Eun Lee, Dahye Lee, Duk Ki Kim, Da Hyun Kang, Chaeuk Chung. Quantitative spatiotemporal analysis of patient-derived organoid-based tumor-immune microenvironment model in lung cancer for immunotherapy response prediction [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 3969.
Abstract 2473: Generative AI improves breast cancer genomic subtype prediction from histology
Authors: Brennan G. Simon, Clemens L. Weiss, Christina Curtis
Journal: Cancer Research (2025)

Abstract Despite advancements in prognostic biomarker identification in cancer, the clinical infeasibility of testing for many biomarkers limits their adoption into clinical practice. Computational pathology has demonstrated remarkable success in efficiently predicting a variety of biomarkers from routine histology images that would otherwise require expensive sequencing or spatial profiling. However, current approaches are limited for data-poor and challenging tasks such as the prediction of genomic subtype in breast cancer. Here, we show that generative AI improves state-of-the-art computational pathology methods by leveraging the power of synthetic data in the task of predicting breast cancer genomic subtype from histology images. Incorporating generative AI to enrich the training dataset improves model AUC, overall accuracy, and accuracy on the underrepresented high risk subtype. Finally, we show that model interpretation using explainable AI techniques on the tile and pixel levels corroborates expected phenotypes as well as identifies previously unknown histologic features associated with genomic subtype. Our results present an improved framework for computational pathology for the enhanced clinical detection and translation of biomarkers. Citation Format: Brennan G. Simon, Clemens L. Weiss, Christina Curtis. Generative AI improves breast cancer genomic subtype prediction from histology [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 2473.
Abstract 5703: NDRG1 enhances cisplatin-induced apoptosis by upregulating BMF in ovarian cancer cells
Authors: Yajing Yang, Ananya Banerjee, Linzhou Wang, Na Li, Patrick Stevens, Elsa Wani, Jessica Miao, Aidan Li, Xiaoli Zhang, Qi-En Wang
Journal: Cancer Research (2025)

Abstract Epithelial ovarian cancer (EOC) is the most lethal malignancy of the female reproductive system, with a five-year survival rate of just 32% for patients diagnosed at distant stages, which accounts for over 48% of cases. Although most EOC patients initially achieve a complete response with surgery and chemotherapy, the majority experience relapse, and recurrent tumors often develop resistance to the original drug regimen. Tumor relapse and acquired chemotherapy resistance are primary contributors to the high mortality associated with EOC. Ovarian cancer is a highly heterogeneous disease, exhibiting extensive variability at the molecular, cellular, and clinical levels. This heterogeneity significantly impacts therapeutic responses, particularly to platinum-based chemotherapies such as cisplatin, leading to variable treatment outcomes among patients. To gain deeper insights into the heterogeneity of ovarian cancer cells in response to cisplatin treatment, single-cell RNA sequencing (scRNA-seq) was conducted on spheroid-cultured ovarian cancer cells exposed to cisplatin. Following a two-week treatment period and a subsequent two-week recovery phase, several distinct clusters of cisplatin-surviving ovarian cancer cells were identified, exhibiting enhanced growth advantages. Analysis of the gene expression profiles of the cell clusters revealed that N-myc downstream regulated 1 (NDRG1) is highly expressed in clusters eliminated by cisplatin, whereas its expression is significantly lower in clusters that survive cisplatin treatment. Further investigation demonstrated that NDRG1 plays a critical role in promoting cisplatin-induced apoptosis. RNA sequencing of NDRG1-knockdown cells identified Bcl2 Modifying Factor (BMF) as a downstream target positively regulated by NDRG1. Given that BMF can bind to Bcl2 protein and functions as an apoptotic activator, these findings suggest that ovarian cancer cells with high NDRG1 expression are more susceptible to cisplatin-induced apoptosis due to NDRG1-mediated upregulation of BMF. Citation Format: Yajing Yang, Ananya Banerjee, Linzhou Wang, Na Li, Patrick Stevens, Elsa Wani, Jessica Miao, Aidan Li, Xiaoli Zhang, Qi-En Wang. NDRG1 enhances cisplatin-induced apoptosis by upregulating BMF in ovarian cancer cells [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 5703.
Abstract 6021: Development of JLF025, an anti-mesothelin T cell engager optimized for efficacy and safety
Authors: Xiaodong Xiao, Zhidi Pan, Junjun Liu, Yali Yue, Fengzhi Li, Shusheng Wang, Haiqiu Huang, Kaiyong Yang, Zhangyi Song, Zhenyu Wang, Hua Jiang, Yueqing Xie, Jianwei Zhu
Journal: Cancer Research (2025)

Abstract Mesothelin (MSLN) is a GPI-anchored glycoprotein that is overexpressed in several solid tumors including mesothelioma, pancreatic cancer, ovarian cancer, non-small cell lung cancer, biliary cancer, and triple negative breast cancer with limited expression in normal tissues. This expression profile makes MSLN an attractive target for cancer immunotherapy. m912 antibody that has demonstrated positive effect in CAR T format in clinics is derived from a fully human Fab library. It has a 100% germline sequence, but its binding affinity is relatively poor (KD around 60 nM). To expand applications of the m912 to include the T-cell engager format, we used phage display to improve m912 affinity, and further, developed a bivalent T-cell engaging bispecific format by fusing the humanized OKT3 scFv to the C-terminus of the light chain. When the final lead with a KD of 1.4 nM was incorporated into this format, the resulting bispecific antibody JLF025 showed high potency in T-cell activation and T-cell dependent cytotoxicity in vitro. Interestingly, the cytotoxicity induced by MSLN-490 was not affected by soluble MSLN at a level found in cancer patient sera. Using a co-grafting mouse model in which a mixture of MSLN-positive NCI-N87 cancer cells and human PBMCs was co-injected with JLF025, we demonstrated that JLF025 exhibited a remarkable tumor suppressing activity. The potent tumor suppressing activity was also observed in a xenograft model in which PBMCs were not co-grafted with tumor cells but delivered from the periphery. In addition, combination of MSLN-490 with Atezolizumab or a chemotherapy drug paclitaxel produced a synergistic effect on tumor inhibition and more T cells were found infiltrated into tumors in the combo groups. In hMSLN and hCD3 double knock-in mouse, JLF025 demonstrated acceptable safety profiles. Thus, combination of JLF025 with immune checkpoint inhibitors and chemotherapy drugs represents a promising cancer treatment strategy and could be considered for future clinical trials. Citation Format: Xiaodong Xiao, Zhidi Pan, Junjun Liu, Yali Yue, Fengzhi Li, Shusheng Wang, Haiqiu Huang, Kaiyong Yang, Zhangyi Song, Zhenyu Wang, Hua Jiang, Yueqing Xie, Jianwei Zhu. Development of JLF025, an anti-mesothelin T cell engager optimized for efficacy and safety [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 6021.
Abstract 5724: Dual inhibition of PARP and STAT3 as a novel therapeutic approach for triple-negative breast cancer cells
Authors: Changyou Shi, Li Pan, Satomi Amano, Jiayuh Lin
Journal: Cancer Research (2025)

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer with limited therapeutic options, contributing significantly to patient mortality. This highlights an urgent need for novel treatment strategies. Olaparib, an FDA-approved poly ADP-ribose polymerase (PARP) inhibitor, is effective in human epidermal growth factor receptor (HER2) negative breast cancer, especially in BRCA-mutated subtypes. However, BRCA-mutant TNBC could eventually develop resistance to PARP inhibitors. We recently found that Olaparib treatment induces elevated IL-6 levels in TNBC cells, which may generate resistance to PARP inhibitors and reduce their effectiveness. Furthermore, knockdown of STAT3, a main downstream effector of IL-6 signaling, enhanced TNBC sensitivity to Olaparib. This study explored the combination of Olaparib and a novel orally bioavailable small-molecule STAT3 inhibitor, LLL12B, in human and murine TNBC cell lines. Both Olaparib and LLL12B independently reduced cell viability, migration, and invasion, but their combination demonstrated significantly greater efficacy than either treatment alone. These results support that dual inhibition of PARP and STAT3 is a novel targeted therapeutic strategy for TNBC. Citation Format: Changyou Shi, Li Pan, Satomi Amano, Jiayuh Lin. Dual inhibition of PARP and STAT3 as a novel therapeutic approach for triple-negative breast cancer cells [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 5724.
Abstract 6026: HX016-9, a novel PD1xVEGF BsAb, as a new candidate treatment of solid tumors
Authors: Hang Ke, Tao Yang, Feiyu Peng, Jialing Li, Cen Chen, Lei Zhang, Stephen Xiong, Faming Zhang, Henry Qixiang Li
Journal: Cancer Research (2025)

Abstract With the clinical confirmation of the superior efficacy of AK112, a first-in-class (FIC) PD1xVEGF bispecific antibody (BsAb), in the treatment of NSLCL cancers, over the PD1 monoclonal antibody (mAb), as shown in a head-to-head phase III trial, we set out to engineer a novel and potentially best-in-class (BIC) PD1xVEGF BsAb using a unique PD1 (HX008, an approved PD1-mAb) and a novel VEGF (HX006, a mAb with more favor activity over Avastin) mAb sequences. HX016-9 has 2+2 IgG1 symmetric structure which was constructed by grafting the PD1 binding domain of HX008 onto the N-terminus of HX006. HX016-9 binds PD1 recombinant protein with EC50 of 0.13nM (vs. 0.1nM by HX008) and to VEGF recombinant protein with EC50 of 0.097nM (vs. 0.042 by HX006) in ELISA assay. It also binds similarly to the PD1+ cell line as HX008 with slightly reduced affinity. A reporter bioassay for PD1 function demonstrated that HX016-9 has EC50 of 3.2nM (vs. 1.0nM for HX008), while a reporter- bioassay for the VEGF function demonstrated that HX016-9 has EC50 of 12.6nM (vs. 11.4nM for HX006), confirming HX016-9 designed function in vitro. Interestingly, HX016-9 demonstrated enhanced reporter activity (up to 5x) in the presence of VEGF than those without, while in contrast, no enhancement for HX008 in the presence of VEGF, similarly as reported for the FIC molecule previously. This enhancement could possibly be interpreted by the formation of the VEGF-HX016-9 complex, thus it facilitating efficient cis-binding to these PD1+ cells and higher avidity binding. This further implicates the enhanced PD1 blocking by HX-016-9 in these cells when VEGF presents. In the huPD1-C57/B6-based HuGEMM mouse, HX016 was shown to have stronger anti-tumor activity over the HX008 and HX006 in huPD-L1/huVEGF-MC38 CRC syngeneic CRC tumor, which can be attributed to both PD1- and VEGF-targeting. In a xenograft A549 NSCLC tumor in immunocompromised mice, HX016-9 also caused anti-tumor activity that can be attributed to anti-VEGF function. These activities are comparable or superior to those of the FIC molecule, warranting the HX016-9 candidacy to move into IND-enabling evaluation and further clinical development. Citation Format: Hang Ke, Tao Yang, Feiyu Peng, Jialing Li, Cen Chen, Lei Zhang, Stephen Xiong, Faming Zhang, Henry Qixiang Li. HX016-9, a novel PD1xVEGF BsAb, as a new candidate treatment of solid tumors [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 6026.