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Journal For Immunotherapy of Cancer Feb 2024The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive. We recently developed a transforming growth factor (TGF)β-based immune modulatory...
TGFβ-specific T cells induced by a TGFβ-derived immune modulatory vaccine both directly and indirectly modulate the phenotype of tumor-associated macrophages and fibroblasts.
The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive. We recently developed a transforming growth factor (TGF)β-based immune modulatory vaccine that controlled tumor growth in a murine model of pancreatic cancer by targeting immunosuppression and desmoplasia in the TME. We found that treatment with the TGFβ vaccine not only reduced the percentage of M2-like tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor but polarized CAFs away from the myofibroblast-like phenotype. However, whether the immune modulatory properties of the TGFβ vaccine on TAM and CAF phenotypes are a direct consequence of the recognition and subsequent targeting of these subsets by TGFβ-specific T cells or an indirect consequence of the overall modulation induced within the TME remains unknown. Recognition of M2 macrophages and fibroblast by TGFβ-specific T cells was assessed by ELISpot and flow cytometry. The indirect and direct effects of the TGFβ vaccine on these cell subsets were evaluated by culturing M2 macrophages or fibroblasts with tumor-conditioned media or with T cells isolated from the spleen of mice treated with the TGFβ vaccine or a control vaccine, respectively. Changes in phenotype were assessed by flow cytometry and Bio-Plex multiplex system (Luminex). We found that TGFβ-specific T cells induced by the TGFβ vaccine can recognize M2 macrophages and fibroblasts. Furthermore, we demonstrated that the phenotype of M2 macrophages and CAFs can be directly modulated by TGFβ-specific T cells induced by the TGFβ vaccine, as well as indirectly modulated as a result of the immune-modulatory effects of the vaccine within the TME. TAMs tend to have tumor-promoting functions, harbor an immunosuppressive phenotype and are linked to decreased overall survival in pancreatic cancer when they harbor an M2-like phenotype. In addition, myofibroblast-like CAFs create a stiff extracellular matrix that restricts T cell infiltration, impeding the effectiveness of immune therapies in desmoplastic tumors, such as pancreatic ductal adenocarcinoma. Reducing immunosuppression and immune exclusion in pancreatic tumors by targeting TAMs and CAFs with the TGFβ-based immune modulatory vaccine emerges as an innovative strategy for the generation of a more favorable environment for immune-based therapies, such as immune checkpoint inhibitors.
Topics: Animals; Mice; T-Lymphocytes; Tumor-Associated Macrophages; Transforming Growth Factor beta; Cell Line, Tumor; Fibroblasts; Pancreatic Neoplasms; Phenotype; Vaccines; Tumor Microenvironment
PubMed: 38417917
DOI: 10.1136/jitc-2023-008405 -
Journal For Immunotherapy of Cancer Feb 2024Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive,...
BACKGROUND
Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice.
METHODS
We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4/CD8 ratio), activity in vitro against endosialin and endosialin cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed.
RESULTS
E3K CAR-T cells were active in vitro against both mouse and human endosialin, but not endosialin, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth.
CONCLUSIONS
Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.
Topics: Humans; Mice; Animals; Pericytes; Receptors, Chimeric Antigen; Mice, Inbred C57BL; Neoplasms; T-Lymphocytes; Mice, Knockout; Tumor Microenvironment; Antigens, Neoplasm; Antigens, CD
PubMed: 38413223
DOI: 10.1136/jitc-2023-008608 -
Journal of Pediatric Hematology/oncology Apr 2024Desmoplastic small round cell tumor (DSRCT) is a highly aggressive primitive sarcoma with a 5-year survival rate estimated at only 15% to 30%. Although few curative... (Review)
Review
INTRODUCTION
Desmoplastic small round cell tumor (DSRCT) is a highly aggressive primitive sarcoma with a 5-year survival rate estimated at only 15% to 30%. Although few curative treatment options exist, patients are most often treated with a combination of aggressive chemotherapy, radiation, and surgery. Targeted therapy inhibitors of platelet-derived growth factor A, insulin-like growth factor receptor 1, and vascular endothelial growth factor receptor-2, which are almost uniformly overexpressed in DSRCT, have largely failed in clinical trials. Anlotinib is a multitarget receptor tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor α/β, c-Kit, and Met. In this study, we presented 3 cases of DSRCT treated effectively with anlotinib combined with chemotherapy.
CASE PRESENTATION
Three children DSRCT patients were enrolled from September 2020 to December 2021 and monitored until August 30, 2022. The clinical data were prospectively studied. The peritoneal cancer index classified all 3 patients as stage IV. After surgery, all 3 patients received anlotinib in combination with chemotherapy and reacted to the medication. For all 3 patients, clinical symptoms were substantially eased, and the size of the masses was reduced. Patient 1 and patient 3's progression-free survival had been extended, and anlotinib was continued as a maintenance medication in the 2 patients who were in good health at the end of the follow-up. Patient 2 died of postoperative complications 1 month after second-stage surgery. The main side effects of anlotinib were fatigue and hypertension. However, its toxicity was controllable and tolerable in children patients.
CONCLUSIONS
This is the first report that anlotinib is effective in children with DSRCT. This report may provide an additional option for the treatment of metastatic DSRCT.
Topics: Child; Humans; Desmoplastic Small Round Cell Tumor; Indoles; Quinolines; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 38408140
DOI: 10.1097/MPH.0000000000002836 -
Anais Brasileiros de Dermatologia 2024
Topics: Humans; Skin Neoplasms; Female; Neoplastic Syndromes, Hereditary; Male
PubMed: 38403551
DOI: 10.1016/j.abd.2022.11.007 -
Frontiers in Immunology 2024One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more... (Review)
Review
One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more common, and by the year 2030, it is expected to overtake lung cancer as the second greatest cause of cancer-related death. The poor prognosis can be attributed to a number of factors, including difficulties in early identification, a poor probability of curative radical resection, limited response to chemotherapy and radiotherapy, and its immunotherapy resistance. Furthermore, an extensive desmoplastic stroma that surrounds PDAC forms a mechanical barrier that prevents vascularization and promotes poor immune cell penetration. Phenotypic heterogeneity, drug resistance, and immunosuppressive tumor microenvironment are the main causes of PDAC aggressiveness. There is a complex and dynamic interaction between tumor cells in PDAC with stromal cells within the tumour immune microenvironment. The immune suppressive microenvironment that promotes PDAC aggressiveness is contributed by a range of cellular and humoral factors, which itself are modulated by the cancer. In this review, we describe the role of innate and adaptive immune cells, complex tumor microenvironment in PDAC, humoral factors, innate immune-mediated therapeutic advances, and recent clinical trials in PDAC.
Topics: Humans; Tumor Microenvironment; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Immunotherapy
PubMed: 38384463
DOI: 10.3389/fimmu.2024.1323198 -
Cancer Medicine Jan 2024One of the main reasons for the unsuccessful treatment of pancreatic cancer is the intense desmoplastic pancreatic microenvironment. In the literature, the effects of...
BACKGROUND
One of the main reasons for the unsuccessful treatment of pancreatic cancer is the intense desmoplastic pancreatic microenvironment. In the literature, the effects of mesenchymal stem cells (MSCs) and their inflammatory phenotypes on cancer cells have been a subject of controversy. Therefore, it is crucial to elucidate the underlying mechanisms of this interaction, especially in the context of pancreatic cancer. We aimed to investigate the effects of naive, TLR4-activated, and TLR4-inhibited phenotypes of adipose-derived MSCs (ADMSC) on pancreatic ductal cell line (Panc-1).
METHODS AND MATERIALS
Adipose-derived MSCs were induced into a proinflammatory phenotype using a 0.5 μg/mL dose of TLR4 agonist, while an anti-inflammatory phenotype was generated in ADMSCs using a 25 μg/mL dose of TLR4 antagonist. We observed that the proliferation of Panc-1 cells was inhibited when naive ADMSCs:Panc-1(10:1) and proinflammatory ADMSCs:Panc-1(10:1) were directly cocultured.
RESULTS
In indirect coculture, both naive and proinflammatory ADMSCs exhibited a significant 10-fold increase in their inhibitory effect on the proliferation and colony forming capacity of Panc-1 cells, with the added benefit of inducing apoptosis. In our study, both naive and proinflammatory ADMSCs were found to regulate the expression of genes associated with metastasis (MMP2, KDR, MMP9, TIMP1, IGF2R, and COL1A1) and EMT (CDH1, VIM, ZEB1, and CLDN1) in Panc-1 cells. Remarkably, both naive and proinflammatory ADMSCs demonstrated antitumor effects on Panc-1 cells. However, it was observed that anti-inflammatory ADMSCs showed tumor-promoting effects instead. Furthermore, we observed a reciprocal influence between ADMSCs and Panc-1 cells on each other's proinflammatory cytokine expressions, suggesting a dynamic interplay within the tumor microenvironment.
CONCLUSIONS
These findings underscore the significance of both the naive state and different inflammatory phenotypes of MSCs in the microenvironment and represent a pivotal step toward the development of novel therapeutic approaches for pancreatic cancer. Understanding the intricate interactions between MSCs and cancer cells may open new avenues for targeted interventions in cancer therapy.
Topics: Humans; Toll-Like Receptor 4; Adipose Tissue; Mesenchymal Stem Cells; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Anti-Inflammatory Agents; Tumor Microenvironment
PubMed: 38379331
DOI: 10.1002/cam4.6964 -
BMC Oral Health Feb 2024Desmoplastic fibroma (DF) is an uncommon bone tumor that originates from the mesenchymal tissue and despite being benign, exhibits aggressive behavior locally. The...
Desmoplastic fibroma (DF) is an uncommon bone tumor that originates from the mesenchymal tissue and despite being benign, exhibits aggressive behavior locally. The following report describes the case of a 7-year-old boy with a rapidly enlarging swelling on the right side of the mandible. After a thorough clinical examination, radiographic imaging, and histopathological analysis, the diagnosis of DF was confirmed. Treatment planning was formulated considering both the tumor's tendency for local recurrence and the patient's well-being. Due to the patient's young age, segmental resection was not deemed appropriate, and an aggressive curettage and enucleation of the lesion followed by the bone graft was performed instead. The patient was kept under close follow-up for the first month of post-surgery and later reviewed after 3, 6, 9, and 12 months, respectively. Good bone healing was observed on radiographs. The patient did not show any signs of recurrence based on clinical or radiographic assessments and did not exhibit any neurosensory deficits as well.
Topics: Male; Humans; Child; Fibroma, Desmoplastic; Mandible; Radiography; Bone Transplantation
PubMed: 38378640
DOI: 10.1186/s12903-024-04018-x -
JAAD International Jun 2024Cutaneous squamous cell carcinoma is a significant cause of morbidity for immunosuppressed patients such as organ transplant recipients; however, histological parameters...
BACKGROUND
Cutaneous squamous cell carcinoma is a significant cause of morbidity for immunosuppressed patients such as organ transplant recipients; however, histological parameters which predict the likelihood of tumor progression are typically based on general population studies in which immunosuppressed patients represent only a small fraction of cases.
OBJECTIVES
To determine the histological parameters which have independent prognostic value for cutaneous squamous cell carcinoma arising in renal transplant recipients.
METHODS
Case-control study incorporating a retrospective blinded histological review of 70 archived specimens of cutaneous squamous cell carcinoma diagnosed in renal transplant recipients, comprising 10 cases where the tumor had progressed and 60 controls.
RESULTS
Progression was significantly associated with head and neck location, size, depth, poor histological grade, perineural invasion (including small caliber perineural invasion), lymphovascular invasion, and a desmoplastic growth pattern.
LIMITATIONS
The retrospective nature and the low number of cases compared to controls.
CONCLUSION
In immunosuppressed patients both small caliber perineural invasion and a desmoplastic growth pattern may also have prognostic significance in addition to other histological parameters already recognized in formal staging schemes.
PubMed: 38371661
DOI: 10.1016/j.jdin.2023.11.010 -
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