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Journal of Translational Medicine Oct 2023Pancreatic ductal adenocarcinoma (PDAC) is characterised by limited responses to chemoimmunotherapy attributed to highly desmoplastic tumor microenvironment. Disrupting...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is characterised by limited responses to chemoimmunotherapy attributed to highly desmoplastic tumor microenvironment. Disrupting the tumor-stromal cell crosstalk is considered as an improved PDAC treatment strategy, whereas little progress has been made due to poor understanding of its underlying mechanism. Here, we examined the cellular role of melanoma associated antigen A isoforms (MAGEA) in regulating tumor-stromal crosstalk mediated chemoresistance.
METHODS
We used clinical samples to explore the correlation between MAGEA expression and patient prognosis in multiple cancers. We utilized cancer cell lines, patient derived organoids and orthotopic PDAC model to examine the function of MAGEA in chemoresistance. We performed biochemical, proteome profiler array and transcriptional analysis to uncover a mechanism that governs tumor-stromal crosstalk. We developed a multi-MAGEA antigen targeted DNA vaccine and tested its effect on PDAC tumor growth.
RESULTS
We establish MAGEA as a regulator of the tumor-stromal crosstalk in PDAC. We provide strong clinical evidence indicating that high MAGEA expression, including MAGEA2, MAGEA3 and MAGEA10, correlates with worse chemotherapeutic response and poor prognosis in multiple cancers, while their expression is up-regulated in chemoresistant PDAC patient derived organoids and cancer cell lines. Mechanistically, MAGEA2 prohibits gemcitabine-induced JNK-c-Jun-p53 mediated cancer cell apoptosis, while gemcitabine stimulated pancreatic stellate cells secretes GDF15 to further enhance the gemcitabine resistance of MAGEA2 expressing cells by activating GFRAL-RET mediated Akt and ERK1/2 dependent survival pathway. Strikingly, immunization with a DNA vaccine that targeting multiple MAGEA antigens, including MAGEA2, MAGEA3 and MAGEA10, elicits robust immune responses against the growth of gemcitabine resistant tumors.
CONCLUSIONS
These findings suggest that targeting MAGEA-mediated paracrine regulation of chemoresistance by immunotherapy can be an improved pancreatic cancer treatment strategy.
Topics: Humans; Vaccines, DNA; Deoxycytidine; Cell Line, Tumor; Pancreatic Neoplasms; Gemcitabine; Carcinoma, Pancreatic Ductal; Immunization; Stromal Cells; Drug Resistance, Neoplasm; Tumor Microenvironment
PubMed: 37814317
DOI: 10.1186/s12967-023-04519-3 -
Frontiers in Immunology 2023Activation of pancreatic stellate cells (PSCs) to cancer-associated fibroblasts (CAFs) is responsible for the extensive desmoplastic reaction observed in PDAC stroma: a...
Activation of pancreatic stellate cells (PSCs) to cancer-associated fibroblasts (CAFs) is responsible for the extensive desmoplastic reaction observed in PDAC stroma: a key driver of pancreatic ductal adenocarcinoma (PDAC) chemoresistance leading to poor prognosis. Specialized pro-resolving mediators (SPMs) are prime modulators of inflammation and its resolution, traditionally thought to be produced by immune cells. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid mediator profiling PSCs as well as primary human CAFs express enzymes and receptors to produce and respond to SPMs. Human PSC/CAF SPM secretion profile can be modulated by rendering these cells activated [transforming growth factor beta (TGF-β)] or quiescent [all- retinoic acid (ATRA)]. ATRA-induced nuclear translocation of arachidonate-15-lipoxygenase (ALOX15) was linked to increased production of n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5), among other SPMs. Inhibition of RvD5 formation increases cancer cell invasion, whereas addback of this molecule reduced activated PSC-mediated cancer cell invasion. We also observed that circulating concentrations of RvD5 levels were decreased in peripheral blood of metastatic PDAC patients when compared with those measured in plasma of non-metastatic PDAC patients. Together, these findings indicate that RvD5 may regulate cancer-stroma cross-talk and invasion.
Topics: Humans; Arachidonate 15-Lipoxygenase; Pancreatic Stellate Cells; Chromatography, Liquid; Tandem Mass Spectrometry; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Tretinoin; Neoplasm Invasiveness
PubMed: 38035115
DOI: 10.3389/fimmu.2023.1248547 -
Journal For Immunotherapy of Cancer Mar 2024The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our...
BACKGROUND
The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients.
METHODS
The 3+3 dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×10 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m). The phase II segment focused on patients with NB at the dose 3 level of 160×10 GD2BATs/kg/infusion.
RESULTS
Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines.
CONCLUSIONS
This study demonstrated the safety of GD2BATs up to 160×10 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.
Topics: Child; Humans; T-Lymphocytes; Neuroblastoma; Antibodies, Monoclonal; Antineoplastic Agents; Osteosarcoma
PubMed: 38519053
DOI: 10.1136/jitc-2023-008744 -
Biomedicines Mar 2024Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC,... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC, characterized by intense stromal desmoplastic reactions and a dominant presence of cancer-associated fibroblasts (CAFs), significantly contributes to therapeutic resistance. However, within the heterogeneous CAF population, fibroblast activation protein (FAP) emerges as a promising target for Gallium-68 FAP inhibitor positron emission tomography (Ga68FAPI-PET) imaging. Notably, 68Ga-FAPI-PET demonstrates promising diagnostic sensitivity and specificity, especially in conjunction with low tracer uptake in non-tumoral tissues. Moreover, it provides valuable insights into tumor-stroma interactions, a critical aspect of PDAC tumorigenesis not adequately visualized through conventional methods. The clinical implications of this innovative imaging modality extend to its potential to reshape treatment strategies by offering a deeper understanding of the dynamic TME. However, while the potential of 68Ga-FAPI-PET is evident, ongoing correlative studies are essential to elucidate the full spectrum of CAF heterogeneity and to validate its impact on PDAC management. This article provides a comprehensive review of CAF heterogeneity in PDAC and explores the potential impact of 68Ga-FAPI-PET on disease management.
PubMed: 38540204
DOI: 10.3390/biomedicines12030591 -
Signal Transduction and Targeted Therapy Feb 2024Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15a PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.
Topics: Humans; Animals; Mice; MicroRNAs; Fos-Related Antigen-2; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; TOR Serine-Threonine Kinases; Tumor Microenvironment; Receptor, IGF Type 1
PubMed: 38342897
DOI: 10.1038/s41392-024-01740-4 -
Cancer Letters Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the associated deaths. Most patients with PDAC show poor response to therapies making the clinical management of this cancer difficult. Stromal cells in the tumor microenvironment (TME) contribute to the development of resistance to therapy in PDAC cancer cells. Cancer-associated fibroblasts (CAFs), the most prevalent stromal cells in the TME, promote a desmoplastic response, produce extracellular matrix proteins and cytokines, and directly influence the biological behavior of cancer cells. These multifaceted effects make it difficult to eradicate tumor cells from the body. As a result, CAF-targeting synergistic therapeutic strategies have gained increasing attention in recent years. However, due to the substantial heterogeneity in CAF origin, definition, and function, as well as high plasticity, majority of the available CAF-targeting therapeutic approaches are not effective, and in some cases, they exacerbate disease progression. This review primarily elucidates on the effect of CAFs on therapeutic efficiency of various treatment modalities, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Strategies for CAF targeting therapies are also discussed.
Topics: Humans; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Tumor Microenvironment; Immunotherapy; Animals; Molecular Targeted Therapy
PubMed: 38615928
DOI: 10.1016/j.canlet.2024.216859 -
Journal of Nuclear Medicine : Official... Feb 2024Accurate diagnosis and staging are crucial for selecting treatment for patients with pancreatic ductal adenocarcinoma (PDAC). The desmoplastic responses associated with...
Accurate diagnosis and staging are crucial for selecting treatment for patients with pancreatic ductal adenocarcinoma (PDAC). The desmoplastic responses associated with PDAC are often characterized by hypometabolism. Here, we investigated F-fibroblast activation protein inhibitor (FAPI)-04 PET/CT in evaluation of PDAC and compared the findings with those obtained using F-FDG. Sixty-two PDAC patients underwent F-FAPI-04 PET/CT and F-FDG PET/CT. Identification of primary lesions, lymph node (LN) metastasis, and distant metastasis (DM) by these methods was evaluated, and TNM staging was performed. Correlation between SUV of the primary lesion and treatment response was explored in patients who received systemic therapy. F-FAPI-04 PET/CT identified all patients with PDAC; F-FDG PET/CT missed 1 patient. Tracer uptake was higher in F-FAPI-04 PET/CT than in F-FDG PET/CT in primary tumors (10.63 vs. 2.87, < 0.0001), LN metastasis (2.90 vs. 1.43, < 0.0001), and DM (liver, 6.11 vs. 3.10, = 0.002; peritoneal, 4.70 vs. 2.08, = 0.015). The methods showed no significant difference in the T staging category, but the N and M values were significantly higher for F-FAPI-04 PET/CT than for F-FDG PET/CT ( = 0.002 and 0.008, respectively). Thus, 14 patients were upgraded, and only 1 patient was downgraded, by F-FAPI-04 PET/CT compared with F-FDG PET/CT. A high SUV of the primary tumor did not correlate with treatment response for either F-FAPI-04 or F-FDG. F-FAPI-04 PET/CT performed better than F-FDG PET/CT in identification of primary tumors, LN metastasis, and DM and in TNM staging of PDAC.
Topics: Humans; Positron Emission Tomography Computed Tomography; Pancreatic Neoplasms; Fluorodeoxyglucose F18; Adenocarcinoma; Carcinoma, Pancreatic Ductal; Lymphatic Metastasis; Gallium Radioisotopes; Quinolines
PubMed: 38176719
DOI: 10.2967/jnumed.123.266283 -
Frontiers in Immunology 2024Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and... (Review)
Review
Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.
Topics: Humans; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Signal Transduction; Immunomodulation
PubMed: 38361931
DOI: 10.3389/fimmu.2024.1287459 -
BioRxiv : the Preprint Server For... Sep 2023Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant...
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
PubMed: 37745372
DOI: 10.1101/2023.09.12.557260 -
Heliyon Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is an extremely life-threatening malignancy with a relatively unfavorable prognosis. The early occurrence of metastasis and local... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is an extremely life-threatening malignancy with a relatively unfavorable prognosis. The early occurrence of metastasis and local recurrence subsequent to surgery contribute to the poor survival rates of PDAC patients, thereby limiting the effectiveness of surgical intervention. Additionally, the desmoplastic and immune-suppressive tumor microenvironment of PDAC diminishes its responsiveness to conventional treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Therefore, it is imperative to identify novel therapeutic targets for PDAC treatment. Chemical modifications are prevalent in various types of RNA and exert significant influence on their structure and functions. RNA modifications, exemplified by mA, mC, mA, and Ψ, have been identified as general regulators of cellular functions. The abundance of specific modifications, such as mA, has been correlated with cell proliferation, invasion, migration, and patient prognosis in PDAC. Pre-clinical data has indicated that manipulating RNA modification regulators could enhance the efficacy of chemotherapy, radiotherapy, and immunotherapy. Therefore, targeting RNA modifications in conjunction with current adjuvant or neoadjuvant therapy holds promise. The objective of this review is to provide a comprehensive overview of RNA modifications in PDAC treatment, encompassing their behaviors, mechanisms, and potential treatment targets. Therefore, it aims to stimulate the development of novel therapeutic approaches and future clinical trials.
PubMed: 37928039
DOI: 10.1016/j.heliyon.2023.e20969