Cancer research最新文献

{"title":"Abstract B032: Targeting Lipid Rafts in Hypoxic Pancreatic Ductal Adenocarcinoma: Preclinical Evaluation of [225Ac]CLR 121225, a Novel Actinium-Based Radio-Conjugate","authors":"Jarrod Longcor, Randall Hoover, Maria Banach","doi":"10.1158/1538-7445.pancreatic25-b032","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b032","url":null,"abstract":"Pancreatic ductal carcinoma (PDAC) has a 5 year survival of <10%. One hallmark of PDAC’s tumor microenvironment is dense desmoplasia, due to abnormal accumulation of extracellular matrix and proliferative fibroblasts, resulting in desmoplasia hypovascularity and a hypoxic environment requiring the tumor cells to use lipids from the microenvironment. Lipid rafts (LR) are highly ordered cell membrane regions composed of cholesterol, sphingolipids and transmembrane signaling receptors and transporters that transport lipids into the cell. LRs are generally enriched in tumor cell membranes versus normal cells (at least 10-fold higher) and even more so in hypoxic environments. Here, we disclose [225Ac]CLR 121225 (CLR 225), a novel actinium-based radio-conjugate uniquely designed to target LRs and enter the tumor cell. CLR 225 safety and efficacy was tested in three mouse subcutaneous xenograft models of human pancreatic cancer: MIA PaCa-2 (MP), PANC-1 (P), and BxPC-3 (BP). Assessments included tumor volume calculation using caliper measurements, body weight measurements, and clinical observations. Animals were euthanized if tumor burden reached >2000 mm3. The single-dose, multiple-level IV plasma pharmacokinetics of unlabeled CLR 225 was determined in mice, rats and dogs. A GLP multiple-dose IV toxicity study of unlabeled CLR 225 at three dose levels in excess of the anticipated human equivalent dose was performed in dogs. Single IV doses of CLR 225 were used in MP and P models at total radioactive amounts of 100, 250, or 500nCi. In the BP model, single IV doses of CLR 225 were given at 250, or 500nCi, and two IV doses of 500nCi on Days 0 and 14. In all models, dose-dependent inhibition of tumor growth was observed as were significant increases in time to progression/survival. In the MP and P models tumor growth was significantly suppressed at all doses with statistically significant tumor volume reduction occurring at doses of 250 and 500 nCi (single doses). This resulted in a survival benefit and reduced growth rate post-decay of the isotope in all treated dose groups. Exponential growth rates were significantly reduced in all treatment groups in BP model with increased growth inhibition occurring with two doses of 500nCi compared to a single dose and resulting in a further survival benefit. This suggests that multiple doses may provide enhanced long-term outcomes. All doses were safe and tolerated based upon body weight and clinical observations. The plasma IV single dose PK of unlabeled CLR 225 was dose-proportional in all three species. Allometric scaling was linear. The multiple-dose toxicity study of unlabeled CLR 225 in dogs was safe with no effects or changes in the measured endpoints. CLR 225 demonstrated in multiple PDAC models significant tumor volume reduction and inhibition of growth resulting in survival benefit, predictable pharmacokinetics, and good safety. Unlabeled CLR 225 exhibited predictable PK and safety in all spec","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"155 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A042: Opioids drive extracellular matrix remodeling in the pancreatic tumor microenvironment","authors":"Kathryn E. Maraszek, Hunter D. Reavis, Arwen A. Tisdale, Xiaozhuo Liu, Eduardo Cortes Gomez, Aleksandr Dolskii, Caneta Brown, Janusz Franco-Barraza, Edna Cukierman, Michael E. Feigin","doi":"10.1158/1538-7445.pancreatic25-a042","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a042","url":null,"abstract":"Pancreatic cancer is a highly lethal malignancy with a 5-year survival rate of 13.3%. The disease is characterized by a dense, desmoplastic stroma comprised of extracellular matrix (ECM) proteins produced by cancer-associated fibroblasts (CAFs). This dense ECM has profound impacts on tumor development and therapy response. In a study conducted by the Pancreatic Cancer Action Network, 93% of pancreatic cancer patients reported experiencing pain, with 83% reporting their pain as moderate-to-severe. Due to the high prevalence of cancer-related pain, 75% of pancreatic cancer patients are prescribed opioids across all stages of disease. Opioids, which predominantly signal through the mu-opioid receptor (MOR), relieve pain through the hyperpolarization of neurons and inhibition of pain transmission in the central nervous system. However, opioids have peripheral effects outside of their analgesic function, such as the commonly experienced opioid-induced side effect of constipation. Importantly, most studies investigating opioids and patient outcomes have correlated opioid use with worsened survival in various cancer types including pancreatic cancer. Despite the wide use of opioids in pancreatic cancer and their association with worse outcome, little is known about how opioids impact tumorigenesis, the ECM, and therapy response. We have discovered that morphine increases expression of collagens and other ECM-related genes in a murine model of pancreatic cancer, and that both pharmacological inhibition and knockdown of MOR in CAFs in vitro reduces RNA and protein expression of type 1a and type 3a collagens. Further, tumors from mice treated with morphine exhibited increased collagen bundling and maturation and were more poorly differentiated, features associated with poor outcome. We developed an ECM-related morphine-induced gene signature which significantly correlated with the basal subtype, as well as poor overall and disease-free survival in pancreatic cancer and several other tumor types. Finally, we have discovered that endogenous opioid peptide precursors are expressed in pancreatic tumor cells and CAFs, capable of driving CAF collagen expression, supporting a potential role for endogenous opioid signaling in regulating collagen and the ECM even in the absence of prescription opioids. Thus, we propose that exogenous and endogenous opioids act on MOR in CAFs to promote ECM remodeling in the pancreatic tumor microenvironment, resulting in more aggressive tumors and worse prognosis. Citation Format: Kathryn E. Maraszek, Hunter D. Reavis, Arwen A. Tisdale, Xiaozhuo Liu, Eduardo Cortes Gomez, Aleksandr Dolskii, Caneta Brown, Janusz Franco-Barraza, Edna Cukierman, Michael E. Feigin. Opioids drive extracellular matrix remodeling in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Se","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"39 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B128: Spatial proteomics extend tumour subtype and microenvironment classifications across genotype-phenotype axes of pancreatic cancer","authors":"Noor Shakfa, Ferris Nowlan, Tiak Ju Tan, Sibyl Drissler, Beth Sunnucks, Jennifer Gorman, Chengxin Yu, Michael Geuenich, Sheng Ben Liang, Barbara Gruenwald, Ayelet Borgida, Cassandra Wong, Brendon Seale, Zhen Yuan Lin, Edward Chen, Golnaz Abazari, Miralem Mrkjonic, Julie Wilson, Kieran Campbell, Anne-Claude Gingras, Rob Grant, Grainne O'Kane, Faiyez Notta, Steve Gallinger, Hartland Jackson","doi":"10.1158/1538-7445.pancreatic25-b128","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b128","url":null,"abstract":"Human pancreatic ductal adenocarcinomas (PDAC) are composed of sparse, heterogeneous tumour cell populations embedded within a dense, desmoplastic stroma and are highly resistant to existing therapies. Guided by underlying genomic aberrations, cancer cell states and phenotypes interact with their microenvironment to shape disease trajectory and therapeutic response. To quantify the cellular phenotypic heterogeneity of these complex tumour-microenvironment interactions we designed custom multiplexed histopathology imaging panels against single cell RNA sequencing-defined tumour, immune, and stromal cell compartments. Using imaging mass cytometry (IMC), we profiled the co-localization and organization of 83 cell types and their functional states in 221 resected pancreatic tumours. This identified extensive inter- and intra-patient heterogeneity including the presence of both classical and basal cell types in most patients and a gradient of pancreatic epithelial identity confirmed by scRNAseq. This single cell content defined an expanded spectrum of classifiable intermediate tumour subtypes between classical and basal which have specific associations to neighboring immune and stroma cellular content, ploidy, established broad transcriptional subtypes, heterogeneity, and patient outcome. Eight reproducible cancer microenvironments were quantified, empowering cross-tumour comparisons. Matched whole genome sequencing (WGS) identified aberrations associated with specific tumour phenotypes and microenvironments. These results support asynchronous tumour and microenvironment genotype-phenotype axes which subdivide basal to classical tumour polarization and categorize co-existing microenvironments from stiff, ECM-rich, immune suppressed to immune infiltrated regions alongside fibrovascularized CD105+ stroma. This is based upon spatially heterogeneous co-occurring microenvironment niches and correlated tumour phenotypes which are associated with KRAS or MYC amplification and CDKN2A or LATS2 deletion on one axis, mutation of epigenetic modifiers in intermediate and hybrid subtypes, and RNF43 deletion on the other axis. To deeply profile the signalling pathways and enriched biological processes characteristic of each tissue state, we performed deep proteomics measurements of each microenvironment and tumor phenotype through whole-slide IMC informed laser capture microdissection and mass spectrometry of 273 micro-regions from a subset of patients. Finally, to identify a robust, minimized set of outcome-relevant features, we used a multi-modal technology optimized machine learning model trained to predict overall survival. We compare the predictive potential of WGS and spatial proteomics and show that a combination of genomic and cellular content outperforms clinical features and platform specific models thereby demonstrating the synergistic benefit of integrated multi-modal data. Our findings classify the spatial organization of human PDAC to identify an inter","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"105 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B023: Repurposing of the SP/NK1R-complex inhibitor aprepitant in hepatopancreatic malignancies","authors":"Matthias Ilmer, Maximilian Viessmann, Bernhard Renz, Frank Braun, Jens Werner","doi":"10.1158/1538-7445.pancreatic25-b023","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b023","url":null,"abstract":"Background: The neurokinin-1 receptor (NK1R) complex, activated by Substance P (SP), has emerged as a promising target. SP promotes cell growth, whereas its antagonist, Aprepitant (AP), used clinically for chemotherapy-induced nausea, has demonstrated anti-tumor activity. However, further insight on the anti-tumoral mechanisms after antagonistic targeting of the complex are required. Methods: We conducted bioinformatical analysis of public as well as own RNAseq data. Assays to assess cell proliferation and cell viability (MTT, scratch assays, colony formation) as well as apoptosis and autophagy were carried out. Metabolic changes were detected by SeaHorse analysis, ROS, NAD+/NADH, and MitoTracker. Results: Patient-derived organoid cultures showed reduced spheroid formation and altered morphology following AP treatment, while SP enhanced spheroid formation. SP promoted proliferation via Rho-kinase-dependent mechanisms and activated the ERK signaling pathway, with AP slightly reducing pERK levels. Further analyses revealed that AP induces apoptosis signaling without subsequent DNA fragmentation. Annexin V/PI staining indicated apoptosis induction after 24 hours, while subG1 analysis suggested a blockade in the apoptosis cascade. Prolonged AP exposure led to necrosis, which was mitigated by co-treatment with N-acetylcysteine. Western blot analysis confirmed caspase-9 and -3 activation but showed no PARP cleavage, likely due to high expression of inhibitors of apoptosis proteins (IAPs), such as XIAP. Conclusion: In conclusion, AP exhibits antiproliferative and cytotoxic effects in pancreatic tumor cells, potentially disrupting an autocrine/paracrine SP-NK1R feedback loop and altering metabolic resilience. Future studies should explore metabolic stress responses and investigate whether co-treatment could overcome incomplete apoptosis activation. Citation Format: Matthias Ilmer, Maximilian Viessmann, Bernhard Renz, Frank Braun, Jens Werner. Repurposing of the SP/NK1R-complex inhibitor aprepitant in hepatopancreatic malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr B023.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"74 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A083: Divergent Roles of TAM Receptors in Tumor and Stromal Compartments of Pancreatic Cancer","authors":"Nancy P. Kren, Alisha Holtzhausen, Doug Graham, Shelton Earp, Yuliya Pylayeva Gupta","doi":"10.1158/1538-7445.pancreatic25-a083","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a083","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options, poor prognosis, and a profoundly immunosuppressive tumor microenvironment (TME). The TAM family of receptor tyrosine kinases—Tyro3, Axl, and MerTK—are known for their roles in maintaining immune homeostasis by promoting the clearance of apoptotic cells in a non-inflammatory manner, thus preventing chronic inflammation and autoimmunity. However, their individual roles in shaping immune tolerance within the TME, especially in the context of cancer, remain unclear and may differ from their tumor-intrinsic functions, where they are often overexpressed. To dissect the host (stromal) contributions of TAM receptors in PDAC, we utilized syngeneic mouse models with targeted deletion of Tyro3 or Axl (tyro3-/- and axl-/- mice). Loss of Tyro3 in the tumor stroma, particularly in myeloid cells, significantly impaired tumor growth and was associated with enhanced type I interferon signaling and upregulation of antigen presentation pathways. In contrast, stromal deletion ofAxl modestly promoted tumor growth and failed to reverse the immunosuppressive TME, as shown by gene expression and flow cytometry analyses. When assessing metastatic potential using a splenic injection model of KPC tumor cells, liver metastases were significantly reduced in tyro3-/- mice. Conversely, stromal loss of Axl led to a marked increase in metastatic outgrowth. Since Axl is known to drive tumor cell proliferation, invasion - and is upregulated in tumor cells resistant to KRAS inhibition - we further explored its role in tumor-intrinsic versus stromal contexts. Axl knockdown in tumor cells alone had no effect on primary tumor growth but completely reversed the increased metastatic phenotype observed in Axl-deficient stroma. These findings reveal distinct and even opposing roles for Tyro3 and Axl within the host immune compartment in PDAC. While Tyro3 promotes immune evasion and tumor progression, Axl’s tumor-intrinsic expression plays a dominant role in driving metastasis. Based on these insights, we are currently testing whether co-targeting Axl and KRAS with small-molecule inhibitors could produce synergistic anti-tumor effects that outweigh potentially adverse TME consequences. Collectively, our data underscores the need to consider the unique, context-dependent roles of individual TAM receptors rather than assuming functional redundancy across the family. Citation Format: Nancy P. Kren, Alisha Holtzhausen, Doug Graham, Shelton Earp, Yuliya Pylayeva Gupta. Divergent Roles of TAM Receptors in Tumor and Stromal Compartments of Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A083.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"51 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A010: Chemotherapy-associated liver damage accelerates pancreatic cancer liver metastasis","authors":"Omar Cortez-Toledo, Kai Liptow, Priyanga Jayakrishnan, Isabella Facchine, Kun Fang, Donovan Drouillard, Michael Poellmann, Mohammed Aldakkak, Susan Tsai, Victor Jin, Michael Dwinell, Nikki Lytle","doi":"10.1158/1538-7445.pancreatic25-a010","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a010","url":null,"abstract":"Pancreatic cancer outcomes remain dismal, even for the ∼15-20% of patients that present with early-stage, surgically resectable disease. Most patients that undergo months of neoadjuvant chemotherapy followed by pancreaticoduodenectomy will recur with metastases within a few years. These clinical challenges illustrate the fact that pancreatic tumor cells spread to distant organs early in disease, and to mitigate metastasis progression, there is a profound need for therapies that target disseminated tumor cells (DTCs). Our studies demonstrate that systemic oxaliplatin (oxali) treatment, a chemotherapy included in the standard-of-care therapy FOLFIRINOX, generates a pro-metastatic liver environment that accelerates pancreatic cancer liver metastasis outgrowth and reduces overall survival in a mouse model. Proteomic analysis of liver interstitial fluid revealed that oxali drives increased expression of Tissue Inhibitor of Metalloproteinases 1 (Timp1). Surgically resected pancreatic cancer patients that recur early have higher serum TIMP1 expression levels at the time of surgery than those that recur late or don’t recur, suggesting that TIMP1 may functionally contribute to metastasis in patients. Furthermore, genetic or pharmacologic blockade of Timp1 reverses the accelerated metastasis phenotype caused by oxali treatment and extends survival in mouse models of pancreatic cancer liver metastasis. Mechanistically, Timp1 is a pleiotropic extracellular protein with multiple functions, including inhibiting matrix metalloproteinases (MMPs) and serving as a cytokine that binds and activates transmembrane receptors. We demonstrate that oxali-damaged livers have decreased functional MMPs, and micrometastases that seed oxali-damaged livers have increased matrix deposition and stiffness. Further, exogenous TIMP1 directly activates Akt-Rheb signaling cascades in pancreatic cancer cells, leading to enhanced migratory and invasive phenotypes. Single-cell sequencing analysis of livers revealed TIMP1 is highly expressed in liver endothelial cells and fibroblasts. Pancreatic cancer cells exposed to conditioned-media from oxali-treated fibroblasts display enhanced migration, which is mitigated in conditioned media from Timp1-suppressed fibroblasts. Taken together, our studies reveal a concerning link between chemotherapy and generation of a Timp1-enriched pro-tumorigenic liver microenvironment capable of promoting metastatic outgrowth. We propose that disrupting Timp1 would serve to reduce recurrence with liver metastasis in surgically-resected patients. Citation Format: Omar Cortez-Toledo, Kai Liptow, Priyanga Jayakrishnan, Isabella Facchine, Kun Fang, Donovan Drouillard, Michael Poellmann, Mohammed Aldakkak, Susan Tsai, Victor Jin, Michael Dwinell, Nikki Lytle. Chemotherapy-associated liver damage accelerates pancreatic cancer liver metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emergi","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"97 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A114: CCK-B Receptor Blockade with Proglumide Enhances Antitumor Activity and Persistence of CD8+CD161+ CAR-T Cells in Pancreatic Ductal Adenocarcinoma","authors":"Nalini Bisht, Keenan J. Ernste, Sharon Amanya. Bright, Harrison Berger, Sruthi Panja, Sujith K. Joseph, Willam K. Decker, Jill P. Smith, Vanaja Konduri","doi":"10.1158/1538-7445.pancreatic25-a114","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a114","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with a 5-year survival rate of only 13%. Resistance to immunotherapy is largely attributed to PDAC’s dense, fibrotic, and highly immunosuppressive tumor microenvironment (TME), which impedes immune cell infiltration and promotes T cell dysfunction. A key contributor to this fibrotic and immunosuppressive landscape is the activation of pancreatic stellate cells and cancer-associated fibroblasts (CAFs) via cholecystokinin-B receptors (CCK-BRs). Proglumide, a selective CCK-BR antagonist, has previously been shown to reduce tumor-associated fibrosis, shift macrophages toward a pro-inflammatory phenotype, enhance CD8+ T cell infiltration, and inhibit metastatic spread. These effects suggest that proglumide may serve as an effective TME-modulating agent to potentiate adoptive cell therapies in PDAC. Concurrently, we identified a subset of human CD8 + T cells expressing CD161 (murine homolog is NK1.1), associated with enhanced cytotoxicity, granzyme B expression, tissue homing, and memory-like phenotype with reduced exhaustion levels. CD8+CD161+ T cells engineered with a HER2-targeted chimeric antigen receptor (CAR) demonstrated significantly improved tumor-killing capacity compared to conventional CAR-T cells in HER2+ PDAC models. In this study, we evaluated the therapeutic potential of combining proglumide with CD8 + CD161 + HER2-directed CAR-T cells in immunodeficient SCID mice bearing either subcutaneous or intraperitoneal luciferase-labeled PANC-1 tumors. Across three independent experiments, combination therapy resulted in significantly reduced tumor burden and improved overall survival compared to monotherapy with either proglumide or CAR-T cells alone (p=0.0120 and p=0.0005, respectively). Bioluminescent imaging confirmed enhanced tumor regression in the combination group, and TME analysis by flow cytometry demonstrated increased CAR-T cell infiltration into the tumors in mice treated with combination therapy. To further evaluate the durability of the response, we performed tumor rechallenge experiments using luciferase-negative PANC-1 cells. Mice that had previously received combination therapy exhibited a trend toward lower tumor burden and delayed tumor growth compared to those that had received CAR-T cells alone. These results suggest that proglumide not only improves CAR-T cell access and function but may also support memory, contributing to long-term tumor control. In conclusion, our findings support a novel immunotherapeutic strategy in PDAC involving pharmacologic remodeling of the TME using CCK-BR blockade in combination with enhanced CAR-T cell products. This approach holds promise for overcoming the immune exclusion and fibrotic barriers characteristic of PDAC, and it may significantly enhance both the efficacy and persistence of adoptive T cell therapies in this challenging disease setting. Further studies are underway to evaluate this strategy in orthotopi","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A061: TIGIT-mediated immune suppression in KMT2D-mutant pancreatic cancer","authors":"Shungang Zhang, Elaina Daniels, Jake McGue, Hongsun C. Kim, Ranga Sudharshan, Dafydd Thomas, Timothy Frankel, Jiaqi Shi","doi":"10.1158/1538-7445.pancreatic25-a061","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a061","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune therapies. There are few biomarkers to guide the selection of patients likely to benefit from available immunotherapyies. Recent whole genome sequencing reveal that KMT2D, a histone-modifying enzyme, is mutated in up to 5% of PDAC cases. Our prior work established a tumor-suppressive role for KMT2D in regulating pancreatic cancer cell plasticity, especially showing that TGF-β-driven microRNA-147b silences KMT2D post-transcriptionally, and that KMT2D loss induces activin A secretion, triggering a noncanonical p38 MAPK pathway and promoting a mesenchymal phenotype. However, the impact of KMT2D deficiency on the tumor microenvironment (TME) remains unexplored. A comprehensive analysis comparing immune composition, immune checkpoint expression, and tumor-immune cell interactions in KMT2D-deficient versus wild-type PDAC has not been performed. Methods: We profiled the immune landscape in human PDAC tissues (n=5 KMT2D-mutant, n=8 wild-type [WT]) using tyramide signal amplification multiplex fluorescent immunohistochemistry (mfIHC) with two distinct antibody panels (Panel 1: PanCK, CD163, PD-L1, CD3, CD8, FoxP3; Panel 2: PanCK, CD163, CD3, CD8, TIGIT, TIM3). Eighty-six tumor-enriched regions were analyzed using InForm Cell Analysis software. For transcriptomic profiling, single-cell RNA sequencing (scRNA-seq) data from 30 PDAC patients were analyzed using the Seurat pipeline. All statistical analyses were conducted in R. Results: KMT2D-mutant PDACs exhibited increased expression of the immune checkpoint TIGIT on CD4 T cells. Cellular engagement analysis demonstrated more CD4 T cells in proximity to epithelial cells (tumor cells) expressed TIGIT in KMT2D-mutant PDACs compared to WT PDACs. Additionally, disrupted immune cell crosstalk, as evidenced by altered spatial correlations in the proximity of antigen presenting cells (APC) to CD4 T cells, and in the distance between tumor cells and CD8 T cells in the mutant tumors. scRNA-seq analyses corroborated the enhanced TIGIT and CTLA4 expression, as well as the upregulation of the exhaustion-associated transcription factor PRDM1 in CD4 T cells from KMT2D-low PDACs, supporting the emergence of a dysfunctional, immunosuppressive CD4 T cell phenotype. Conclusion: Our findings reveal that KMT2D mutations are associated with an immunosuppressive tumor microenvironment in PDAC, marked by CD4 T cell dysfunction and upregulation of the immune checkpoint TIGIT. These results nominate TIGIT as a promising therapeutic target for this subset of PDAC patients and provide new insight into the mechanisms of immunotherapy resistance in KMT2D-mutant tumors. Citation Format: Shungang Zhang, Elaina Daniels, Jake McGue, Hongsun C. Kim, Ranga Sudharshan, Dafydd Thomas, Timothy Frankel, Jiaqi Shi. TIGIT-mediated immune suppression in KMT2D-mutant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advance","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"67 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B123: Phenotypic, Microenvironmental, and Genetic Crosstalk Shapes Pancreatic Cancer Organization","authors":"Ofer Elhanani, Guy Truzman, Martin Wartenberg, Yuval Bussi, Dana Shainshein, Bar Engelberg, Ido Harlev, Adi Lilien, Inti Zlobec, Tamar Geiger, Leeat Keren","doi":"10.1158/1538-7445.pancreatic25-b123","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b123","url":null,"abstract":"Tumors acquire a set of functional capabilities, known as the Hallmarks of Cancer, to thrive and grow. While extensive research has revealed how gene and protein expression networks contribute to these traits, the relationships between tumor cell states, spatial organization of immune and stromal cells in the tumor microenvironment, and tumor genetics, remains poorly understood. To address this, we constructed a cohort of primary tumor tissues from 117 pancreatic ductal adenocarcinoma (PDAC) patients. Using Multiplexed Ion-Beam Imaging (MIBI) with a 40-antibody panel, we mapped the spatial organization of major cell types and their phenotypes. We also conducted targeted genomic and bulk proteomic analyses to explore how spatial organization patterns align with tumor genetics and proteome profiles. We identified phenotypic subtypes of tumor epithelium that shape distinct microenvironmental niches: (i) Glycolytic tumors expressing proteins such as GLUT1, LDHA, MCT1 and HIF1α reside in hypoxic niches. They are encased by dense fibrotic stroma and lacking vasculature and immune cell infiltration. (ii) Tumor and metaplastic epithelium that exhibit an oxidative proteome profile, are highly enriched for ECAD and PD-L1 expression, and are situated near pancreatic epithelium and vasculature, with significant immune infiltration. (iii) Myeloid-interacting tumors expressing CXCL5, heavily infiltrated with neutrophils and characterized by low-collagen and high FAP positive fibroblasts. Notably, neutrophils accumulate within the lumen of tumor ducts where they exhibit increased apoptosis, DNA damage, and netosis. These highly neutrophil-infiltrated tumors, associate with poor disease outcome. The genetic landscape of PDAC influences these spatial and phenotypic patterns. Patients with TGFβ/SMAD pathway mutations, demonstrate an increased proportion of basal tumor cells accompanied by reduced lymphocytic infiltration. Similarly, distinct TP53 variants shape immune-cell infiltration: patients harboring missense mutations show increased lymphocytic infiltration compared to those with truncating mutations. These findings underscore the strong link between tumor genetics, phenotypic heterogeneity and cellular architecture of the PDAC microenvironment, offering new insights into collective tumor behavior. Citation Format: Ofer Elhanani, Guy Truzman, Martin Wartenberg, Yuval Bussi, Dana Shainshein, Bar Engelberg, Ido Harlev, Adi Lilien, Inti Zlobec, Tamar Geiger, Leeat Keren. Phenotypic, Microenvironmental, and Genetic Crosstalk Shapes Pancreatic Cancer Organization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr B123.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"67 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A064: Uncoupling CX3CL1-CX3CR1 Axis in IPMN Development Through Transgenic Mouse Models","authors":"Li Ding, Kaely Roeck, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Esther Rodman, Mark Maynes, Bibo Zhu, Aaron Johnson, Jie Sun, Li Hu, Daniel Billadeau","doi":"10.1158/1538-7445.pancreatic25-a064","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a064","url":null,"abstract":"BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) is one of the two most common precursor lesions leading to the development of pancreatic ductal adenocarcinoma (PDA). IPMNs comprise a heterogeneous group of tumors with a wide range of grades and histotypes, and the emergence of single-cell RNA sequencing (RNA-seq) and multiplex digital spatial profiling have characterized unique cell populations, including dysplastic epithelial and immune cells, within the heterogeneous tumor microenvironment that carry signature gene expressions, which could be used as markers for disease progression. However, it is not clear on the heterogeneity of the epithelial and immune response of the evolution during progression of IPMN to PDA. OBJECTIVE Combining nuclear GSK-3β with oncogenic KRas mice (referred to as KNGC – KRas, nuclear GSK-3β, Cre) resulted in the development of IPMN. We have found that 4-week-old KNGC mice show progressive desmoplasia and ductal lesion development with increased M2-like macrophage infiltration. Interestingly, CX3CL1 (fractalkine), a chemokine involved in the recruitment of CX3CR1-expressing monocytes and M2-like macrophage conversion in various disease models is expressed by IPMN progenitor ductal cells. We aim to investigate expression and contribution of CX3CL1-CX3CL1 axis in the development and progression of IPMN. METHODS We utilized a newly generated CX3CL1-mCherry and well-established CX3CR1-GFP knockin/knockout mouse for crossbreeding with KNGC and KGC (KRas, GNas, Cre) for lineage tracing and function analysis by immunofluorescent staining, flow cytometry and CyTOF. RESULTS Both KNGC- and KGC-3LmCherry/+ mice harbor a large population of CX3CL1-mCherry/EPCAM+ epithelial cells as compared to 3LmCherry/+ and wildtype (WT) control mice. In KNGC and KGC mice, we show that there was a unique population of macrophages (CD45+ CD11b+ Ly6G- F4/80+ Ly6c- ) with significantly higher expression of CX3CR1 (CX3CR1Hi) that was not seen in WT mice. Significantly, Knockout of CX3CR1 in KNGC-3RGFP/GFP animals had a paucity of M2-like macrophages, reduced T regulatory cells (Tregs), substantially reduced desmoplasia and impaired development of IPMN. CONCLUSIONS The study provides important knowledge regarding the role of CX3CL1-CX3CR1 axis in recruitment and generation of M2-like macrophages, and their impact on the initiation of the immune/stroma microenvironment facilitating IPMN development. Further investigations using these models have the potential to identify new biomarkers for risk stratification and therapeutic intervention. Citation Format: Li Ding, Kaely Roeck, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Esther Rodman, Mark Maynes, Bibo Zhu, Aaron Johnson, Jie Sun, Li Hu, Daniel Billadeau. Uncoupling CX3CL1-CX3CR1 Axis in IPMN Development Through Transgenic Mouse Models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformat","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"20 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}