tbuckley/cabot-search huggingface dataset:
Abstract 749: Dynamic change in immune landscape among NSCLC patients who received neo-adjuvant PD-1 treatment
Authors: Zheshen Han, Haoting Shi, Xue Wang, Yufei Wang, Ruixin Pan, Chao Hu, Qing Qu, Rong Cai
Journal: Cancer Research (2025)

Abstract Background: Neoadjuvant immunotherapy in combination with chemotherapy has been approved for resectable lung squamous cell carcinoma (LUSC) patients. However, the dynamic protein changes in the local tumor microenvironment (TME) associated with treatment remains unclear. We sought to spatially profile the treatment-related protein landscape changes in LUSC. Methods: A total of 11 LUSC patients who received 2 to 4 cycles of neoadjuvant PD-1 inhibitors in combination with chemotherapy (nab-paclitaxel and carboplatin) were recruited. Formalin-fixed paraffin-embedded (FFPE) pre-treatment lung biopsy and paired post-operative surgery samples were collected. To investigate the immune landscape change related to neoadjuvant immunotherapy, we utilized the GeoMx Digital Spatial Profiler (DSP) to spatially profile the expression of &amp;gt;570 proteins in tumor- (pan-CK+), immune- (CD45+), and cancer-associated fibroblast (CAF, a-SMA+) regions in pre- and post-treatment specimens. Differential expression analyses, and GSEA were performed. Results: We found that active YAP1, BAX, and IRF3 in the tumor region, and CD11a, CXCR3, and CD34 in the immune region were upregulated after treatment, while Syndecan-1, Tuberin, and PAK1 in the immune region and MEK1, CD3G, and VEGFD in the CAF region were downregulated after treatment (all FDR &amp;lt; 0.05). GSEA highlighted that the neoadjuvant immunochemotherapy downregulated differentiation, HIF1, Insulin, and mTOR pathway (NES: -1.70, -1.76, -1.77, and -1.64, respectively) in immune and CAF regions (all adjusted P &amp;lt; 0.05). Findings suggested that neoadjuvant immunochemotherapy may improve oxygenation via the HIF1 pathway, induce metabolic stress and nutrient depletion via the mTOR and insulin pathways, promote dedifferentiation or epithelial-to-mesenchymal transition, as well as reduce immune evasion by modifying the tumor microenvironment. This study provides clues and preliminary evidence to further understand the treatment mechanism of neoadjuvant immunochemotherapy for LUSC. Conclusion: In this spatial biology study, we found dynamic changes in proteins between pre- and post-neoadjuvant immunochemotherapy among LUSC patients. The dynamic changes revealed some potential impacts of NAT on LUSC, including improving oxygenation, reducing mTOR and insulin activity, and mitigating immune evasion. Understanding these mechanisms can guide the development of combination therapies to improve patient outcome. Citation Format: Zheshen Han, Haoting Shi, Xue Wang, Yufei Wang, Ruixin Pan, Chao Hu, Qing Qu, Rong Cai. Dynamic change in immune landscape among NSCLC patients who received neo-adjuvant PD-1 treatment [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 749.
Abstract 6541: Spatial and longitudinal characterization of tumor microenvironment of peritoneal carcinomatosis: Nab-PIPAC phase IB trial
Authors: Laura Grassi, Raphael Genolet, Valentine Du Bois, Manuela Undurraga, Thibaud Koessler, Jean-Christophe Tille, Antonella Diciola, Mariagrazia Di Marco, Noémie Lang, Nicolas Mach, remi Peanne, Eileen Zhao, Nawel Zouggari, Julie Terzic, Catherine Raimond, Patrick Petignat, Christian Toso, Stefan Monig, Martin Hübner, Frederic Ris, Alexandre Harari, Intidhar Labidi-Galy
Journal: Cancer Research (2025)

Abstract Peritoneal carcinomatosis is a major therapeutic challenge in gynecological and gastrointestinal malignancies, associated with poor quality of life and short survival. Little is known about the tumor microenvironment (TME) of peritoneal carcinomatosis resistant to chemotherapy. Using multiplexed immunohistochemistry (FoxP3, CD163, CD8, CD68, FAP and Cytokeratin) and sensitive T cell receptor (TCR) repertoire analysis, we investigated spatial and longitudinal changes of the TME of 54 biopsies collected from 18 patients with peritoneal carcinomatosis (six ovarian cancer, nine gastric cancer and three pancreatic cancer) treated in the Nab-PIPAC phase IB trial (repeated cisplatin and nab-paclitaxel by pressurized intraperitoneal aerosol chemotherapy [PIPAC]). Overall, tumors were cold with low T cell infiltration. There was high intra- and inter-patient heterogeneity of TCR repertoire and immune cell distribution, with different tumor patterns and TME compositions depending on the primary cancer. Ovarian and gastric cancers were enriched in CD163+ tumor-associated macrophages while pancreatic cancer was enriched in FAP+ cancer-associated fibroblasts and FoxP3+ regulatory T cells. TCR clonality was higher in ovarian cancer, as compared to oesogastric cancer, likely reflecting expansion of tumor reactive T cells. Focusing on ovarian cancer, hyperexpanded T cells were more abundant in the tumor core as compared to matched stroma. Our spatial and longitudinal study brings new insights into the TME of peritoneal carcinomatosis, with implications for the future design of precision medicine in this disease. Citation Format: Laura Grassi, Raphael Genolet, Valentine Du Bois, Manuela Undurraga, Thibaud Koessler, Jean-Christophe Tille, Antonella Diciola, Mariagrazia Di Marco, Noémie Lang, Nicolas Mach, remi Peanne, Eileen Zhao, Nawel Zouggari, Julie Terzic, Catherine Raimond, Patrick Petignat, Christian Toso, Stefan Monig, Martin Hübner, Frederic Ris, Alexandre Harari, Intidhar Labidi-Galy. Spatial and longitudinal characterization of tumor microenvironment of peritoneal carcinomatosis: Nab-PIPAC phase IB trial [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 6541.
Abstract 6144: Peritoneal and omental macrophages provide anti-tumor immunity in an ovarian cancer model
Authors: Joseph R. Dominguez, Jiseon Kim, Seung Hyeon Kim, Yeonwoo Choi, Soroush Tahmasebi, Brahm H. Segal, Burkhard Ludewig, Ki-Wook Kim
Journal: Cancer Research (2025)

Abstract The omentum is a visceral adipose tissue that contains fat-associated lymphoid clusters (FALC) to aid in peritoneal immunity. These clusters consist of large aggregates of B cells, T cells, dendritic cells, macrophages, and innate lymphoid cells that participate in the clearance of pathogens. Tissue-resident macrophages (TRM) are immune cells found in every tissue and their function is influenced by the local tissue microenvironment. TRM can be defined by their origins, consisting of subsets maintained either by embryonic precursors or by bone-marrow progenitors. A recent study found embryonically derived TRM express at least one marker amongst Tim4, LYVE1, FOLR2 while bone marrow derived macrophages maintain CCR2 expression. Previous publications have shown the existence of LYVE1+ macrophages surrounding each cluster, here we study an unexamined subset of FALC-associated macrophages that are imbedded within the lymphoid structures. Using confocal imaging, flow cytometry analysis with reporter/ conditional knock-out mice, we have characterized this TRM subset as CX3CR1+ LYVE1lo/- Tim4- and CCR2 dependent. Through Wt1-driven csf1 deletion, we depleted peritoneal and omental-resident (ORM) and found increased ID8 tumor cells in comparison to littermate controls. Lastly, promotion of CX3CR1+ ORM and reduction of LYVE1+ Tim4- ORM led to reduced tumor growth in the omentum in early-stage tumor challenge. Citation Format: Joseph R. Dominguez, Jiseon Kim, Seung Hyeon Kim, Yeonwoo Choi, Soroush Tahmasebi, Brahm H. Segal, Burkhard Ludewig, Ki-Wook Kim. Peritoneal and omental macrophages provide anti-tumor immunity in an ovarian cancer model [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 6144.
Abstract 2354: Developing a gene signature from circulating biomarkers to forecast Lu-PSMA response in advanced prostate cancer
Authors: Srinivas V. Koduru, Mark Kidd, Alin Chirindel, Nicolas Guillaume, Abdel Halim
Journal: Cancer Research (2025)

Abstract Introduction: 177Lu-PSMA-targeted radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC) leverages the high PSMA expression on cancer cells. The radiolabeled molecule binds to PSMA, delivering beta radiation to selectively destroy cancer cells while sparing surrounding healthy tissue. Despite its sophistication, not all mCRPC patients with adequate PSMA expression respond to this therapy. Currently, there is no mean to predict response or optimize patient selection. We performed transcriptomic profiling on patients undergoing Lu-PSMA therapy, aiming to identify a gene signature that can predict treatment response and help select the most suitable patient population. Methods: Whole blood samples were collected from mCRPC patients receiving Lu-PSMA-based RLT and categorized into three groups based on PCWG3 criteria: Responders (R, n=30), Partial Responders (RR, n=10), and Non-Responders (NR, n=26). Total RNA was isolated and subjected to RNA sequencing using the NovaSeq 6000 platform. Differentially expressed genes were identified through data analysis with Partek Flow, and pathway analysis was performed to investigate associated biological processes. Results: RNA sequencing of the three groups (R, NR, and PR) revealed 825 statistically significant genes (FC &amp;gt; 1; P &amp;lt; 0.05) in the R vs. NR comparison, 1, 807 genes in R vs. PR, and 1, 548 genes in PR vs. NR. Furthermore, over 90% of responders exhibited prolonged survival, while more than 95% of non-responders and over 80% of partial responders were recorded as deceased. Conclusion: Our findings suggest that the identified gene signature could serve as a predictive biomarker for clinical response prior to initiating 177Lu-PSMA treatment. Additionally, the pronounced expression of certain genes in non-responders presents an opportunity for the development of novel therapeutic strategies. Citation Format: Srinivas V. Koduru, Mark Kidd, Alin Chirindel, Nicolas Guillaume, Abdel Halim. Developing a gene signature from circulating biomarkers to forecast Lu-PSMA response in advanced prostate 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 2354.
Izalontamab (SI-B001), a novel EGFRxHER3 bispecific antibody in patients with Locally Advanced or Metastatic Epithelial Tumor: Results from first-in-human phase I/Ib study
Authors: Jinhui Xue, Yuxiang Ma, Yuanyuan Zhao, Yongsheng Wang, Wei Hong, Yan Huang, Yunpeng Yang, Wenfeng Fang, Shaodong Hong, Yang Zhang, Qianwen Liu, Yi Zhu, Hai Zhu, Sa Xiao, Li Zhang, Hongyun Zhao
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Izalontamab (SI-B001) is a novel EGFR×HER3 bispecific antibody. This first-in-human phase I study presents the safety and pharmacokinetics of izalontamab. Patients and Methods: Previously treated patients with locally advanced or metastatic epithelial tumors were enrolled in the dose-escalation or dose-expansion phases. The dose-escalation phase consisted of an accelerated titration and a "3+3" design with 9 dose levels from 0.4 to 28.0 mg/kg. The dose-expansion phase included 5 dose levels from 6.0 to 21.0 mg/kg. Izalontamab was administered intravenously weekly(QW) or every two weeks(Q2W) in a four-week cycle. Available pre-treatment specimens were obtained to explore the relationship between EGFR/HER3 expression and efficacy. Results: 60 patients were enrolled. Among the 60 enrolled patients, 49 had non-small cell lung cancer(NSCLC), 6 had nasopharyngeal cancer, 3 had head and neck cancer(HNSCC), and 2 had other types of cancer. The most common treatment-related adverse events were rash (42%), paronychia (25%) and infusion-related reactions (23%). No drug-related death occurred. Izalontamab displayed non-linear pharmacokinetic behavior and clearance at steady state appeared to be approaching a dose-independent value at 6 mg/kg and above. The best response included 2 confirmed partial responses in NSCLC and HNSCC patients; 18 patients had stable disease, including NSCLC(n = 17) and colorectal cancer(n=1). The recommended phase 2 dose for izalontamab was determined as 9-16mg/kg QW weekly. Conclusions: Izalontamab was well tolerated and demonstrated preliminary antitumor activity in patients with locally advanced or metastatic epithelial tumors, supporting it as a promising therapeutic candidate for combination therapies, with a phase 3 study currently underway.
Abstract 6168: CAF-mediated cancer immunotherapy resistance can be overcome via selective inhibition of NOX 2 and 4
Authors: Jihyun Um, Heesu Kim, Hyeji Jang, Eun Sil Lee, Sung Hwan Moon, Soo Jin Lee
Journal: Cancer Research (2025)

Abstract Cancer-associated fibroblasts (CAFs) are a functionally heterogeneous population that constitutes tumor stroma. CAFs interact with cancer cells and immune cells by secreting various chemokines/cytokines, participating in extracellular matrix (ECM) remodeling and affecting the immune invasion in the tumor microenvironment (TME). Finally, CAFs promote tumor growth and induce resistance to chemotherapy or immunotherapy, making tumors more aggressive associated with poor prognosis in various types of solid tumors. The primary function of NADPH oxidases (NOXs) is to produce reactive oxygen species (ROS). NOX enzymes, which are clinically upregulated in CAFs, have been reported to be critical effectors of tumor fibrosis and immunosuppression of the TME. It suggests that modulation of CAF-mediated immunosuppression via NOX regulation could be a potential strategy for cancer immunotherapy. In this study, NOX2 and 4 are markedly increased in human pancreatic CAFs (pCAFs) compared to human pancreatic fibroblasts (PFs) and knockdown of NOX2 or 4 effectively decreased fibrosis-related markers and immune cytokines/chemokines in pCAFs, respectively. In order to confirm the importance of NOX in CAF functions, we utilized compound-19, a selective NOX inhibitor. Com-19 treatment significantly reduced the expression of fibrosis-related factors and immune cytokines/chemokines in pCAFs. In addition, com-19 inhibited monocyte infiltration and their differentiation into M2 macrophages in CAF-rich tumor-mimicking 3D spheroids in vitro. The in vivo efficacy was evaluated using a CAF-rich colorectal cancer mouse model. Com-19 inhibited tumor fibrosis and immune cytokines in CAF-rich tumors via NOX inhibition. Importantly, com-19 increased the intratumoral infiltration of CD8+ T cells, resulting in excellent synergistic tumor growth inhibition when co-administered with immune check inhibitors (ICIs) in the model which poorly responses to ICIs. Taken together, the results support that NOXs play a crucial role in CAF-mediated ICIs resistance in cancers and NOX inhibition can be a promising strategy to overcome the resistance. Com-19 effectively regulated the fibrotic and immune-suppressive properties of CAF-rich tumors via NOX inhibition. Therefore, com-19 can potentiate cancer immunotherapy by overcoming CAF-Mediated ICIs resistance. GLP safety/toxicity studies of com-19 have been completed and phase 1 clinical studies are scheduled in 1Q, 2025. Citation Format: Jihyun Um, Heesu Kim, Hyeji Jang, Eun Sil Lee, Sung Hwan Moon, Soo Jin Lee. CAF-mediated cancer immunotherapy resistance can be overcome via selective inhibition of NOX 2 and 4 [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 6168.
Abstract 3325: PELO is a synthetic lethal target in FOCAD deleted cancers
Authors: Michelle Patricia Cicchini, Yang Peng, Yanhua Rao, Biju Mangatt, Benjamin Schwartz
Journal: Cancer Research (2025)

Abstract During protein translation, ribosomes may stall for a number of reasons including the presence of mRNA defects, cell stress, nonoptimal codon clusters, ribosome collisions, etc. One mechanism of resolving these stalled ribosomes is to extract the mRNA using the SKI complex. Focadhesin (FOCAD) provides an essential function to the SKI complex by stabilizing and protecting SKI proteins from degradation, but it is also a common collateral deletion with CDKN2A- and MTAP-loss in many cancers. In the absence of a functional SKI complex, stalled ribosomes are resolved via the No-go decay (NGD) pathway which leverages PELO (protein pelota homolog), HBS1L (HBS1-like protein), and ABCE1 (ATP-binding cassette sub-family E member 1) . Together PELO and HBS1L recognize stalled ribosomes and recruit ABCE1 to split and recycle ribosomal subunits. Consistent with the NGD pathway compensating for the loss of a functional SKI complex in normal cells, unbiased whole-genome knockout screens identify FOCAD-deleted cell lines to be dependent on PELO for their survival. In this work, PELO-dependency is validated in FOCAD-deleted cancer cell lines and it is demonstrated that FOCAD-deletion drives PELO-dependency. Furthermore, it is shown that PELO-knockout induces ribosomal readthrough, GCN2 activation, and EIF2α induction in FOCAD-deleted cell lines prior to the robust anti-proliferative and apoptotic readouts observed at longer timepoints. Together, these data support that loss of PELO in FOCAD-deleted cancer cells is synthetic lethal due to the persistence of stalled ribosomes that initially activate cell survival pathways but ultimately lead to cell death. Citation Format: Michelle Patricia Cicchini, Yang Peng, Yanhua Rao, Biju Mangatt, Benjamin Schwartz. PELO is a synthetic lethal target in FOCAD deleted cancers [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 3325.
Abstract 6793: Characterizing glucose transport at incremental stages of chemoresistance in melanoma
Authors: Emily T. Wang, Abbey Michaelson, Amy E. Nielson, Rock J. Mancini
Journal: Cancer Research (2025)

Abstract Multidrug resistance (MDR) presents major challenges in cancer treatment as cancer cells evolve to evade the effects of chemotherapy. This resistance is driven by various cellular mechanisms, including the overproduction of transport proteins that regulate the intake of essential nutrients and the removal of xenobiotics. While the mechanisms underlying drug efflux in MDR cancers are well studied, the role of carbohydrate transport proteins, like glucose transporters (GLUTs), remains poorly characterized as cells become increasingly resistant to chemotherapy. As interest grows in using glycoconjugation for targeted drug delivery, understanding how sugar transport and metabolism are altered in MDR cancers could be crucial for enhancing the specificity and efficiency of these strategies. In this study, we investigated GLUT expression in a melanoma cell line (B16-F10-Luc2) that was subjected to incremental concentrations of the anthracycline doxorubicin (DOX), ranging from 1 nM to 1 μM. As the cells acquired an MDR phenotype, we observed increased efflux activity and decreased cell proliferation rates. At the proteomic level, our analysis showed that GLUT1 and GLUT3 remain stable over the range of resistance levels, while GLUT2 exhibited minimal expression. Interestingly, GLUT4 was transiently upregulated at the 1 μM resistance level and demonstrated insulin responsiveness. We then evaluated GLUT activity and functionality by comparing glucose uptake under normal and starvation conditions and found that glucose deprivation had a limited impact on uptake in both non-resistant and resistant melanoma. To gain a comprehensive analysis into the genomic regulation of GLUTs and metabolic factors associated with MDR, we performed RNA-seq to reveal differential gene expression across various intermediate levels of DOX resistance. Collectively, our findings provide insights into the modular metabolic adaptations of MDR cancers, which could aid in the development of targeted therapies that address GLUT-related defects with drug resistance. Citation Format: Emily T. Wang, Abbey Michaelson, Amy E. Nielson, Rock J. Mancini. Characterizing glucose transport at incremental stages of chemoresistance in melanoma [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 6793.
Abstract 2353: CRHBP, a novel multiple cancer biomarker connected with better prognosis and anti-tumorigenicity
Authors: Wonbeak Yoo, Yeeun Lee, Kyung Chan Park, Hyunji Choi
Journal: Cancer Research (2025)

Abstract Corticotropin-releasing hormone-binding protein (CRHBP) is a key modulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a crucial role in stress responses, immune regulation, and neuroendocrine functions. Despite its importance in physiological processes, the role of CRHBP in tumor biology and its clinical relevance remain largely unknown. This study aims to comprehensively investigate CRHBP expression across diverse cancer types, its prognostic significance, and its potential molecular mechanisms in tumor progression. We show that CRHBP expression was consistently downregulated in the majority of solid tumors, with the most significant reductions observed in LUAD, LIHC, and KIRC. Low CRHBP expression was strongly correlated with poor prognosis, including shorter OS and DFS, in multiple tumor types. Methylation analysis revealed that hypermethylation of the CRHBP promoter region was associated with its downregulation in several cancers. Further, we identified a set of miRNAs (miR-21, miR-155, miR-29a, and miR-181a) that were upregulated in these tumors and may contribute to the suppression of CRHBP expression. Gene enrichment analysis revealed that CRHBP is involved in key cellular processes, including intracellular signal transduction, metabolic regulation, and hormone-related pathways. CRHBP expression also showed significant correlations with the immune microenvironment, particularly with the infiltration of regulatory T cells (Tregs), macrophages, and dendritic cells. PPI network analysis indicated that CRHBP interacts with several proteins involved in the stress response, immune regulation, and cellular metabolism. Functionally, overexpression of CRHBP inhibited tumor cell proliferation in LUAD, LIHC, and KIRC cell lines, as measured by MTT and colony formation assays. Furthermore, CRHBP overexpression significantly reduced cell migration and invasion in KIRC and hepatocellular carcinoma (HCC) cell lines. Together, these data demonstrated that CRHBP expression is associated with tumor progression, immune cell infiltration, and key molecular pathways. Overexpression of CRHBP inhibits cell proliferation and mobility in multiple cancers, suggesting its potential as a biomarker and therapeutic target in cancer. Citation Format: Wonbeak Yoo, Yeeun Lee, Kyung Chan Park, Hyunji Choi. CRHBP, a novel multiple cancer biomarker connected with better prognosis and anti-tumorigenicity [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 2353.