ABSTRACT
Solid tumors elicit suppressive T cell responses which impair antigen-presenting cell (APC) functions. Such immune suppression results in uncontrolled tumor growth and mortality. Addressing APC dysfunction, dendritic cell (DC)-mediated anti-tumor vaccination was extensively investigated in both mice and humans. These studies never achieved full resistance to tumor relapse. Herein, we describe a repetitive RM-1 murine tumor rechallenge model for recurrence in humans. Using this newly developed model, we show that priming with tumor antigen-pulsed, Toll-like receptor (TLR)2 ligand-activated DCs elicits a host-protective anti-tumor immune response in C57BL/6 mice. Upon stimulation with the TLR2 ligand peptidoglycan (PGN), the tumor antigen-pulsed DCs induce complete resistance to repetitive tumor challenges. Intra-tumoral injection of PGN reduces tumor growth. The tumor resistance is accompanied by increased expression of interleukin (IL)-27, T-box transcription factor TBX21 (T-bet), IL-12, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, along with heightened cytotoxic T lymphocyte (CTL) functions. Mice primed four times with PGN-stimulated tumor antigen-pulsed DCs remain entirely resistant to repeat challenges with RM-1 tumor cells, suggesting complete prevention of relapse and recurrence of tumor. Adoptive transfer of T cells from these mice, which were fully protected from RM-1 rechallenge, confers anti-tumor immunity to syngeneic naive recipient mice upon RM-1 challenge. These observations indicate that PGN-activated DCs induce robust host-protective anti-tumor T cells that completely resist tumor growth and recurrence.
Subject(s)
Cancer Vaccines/immunology , Dendritic Cells/immunology , Immunotherapy, Adoptive/methods , Prostatic Neoplasms/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Antigens, Neoplasm/immunology , Antigens, Neoplasm/metabolism , Cytokines/metabolism , Dendritic Cells/transplantation , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred C57BL , Neoplasm Recurrence, Local , Peptidoglycan/metabolism , Toll-Like Receptor 2/agonists , Tumor BurdenABSTRACT
OBJECTIVE: To compare internal target volume (ITV) generated using population-based displacements (ITV_study) with empty and full bladder scan fusion (ITV_EBFB) for organ-at-risk (OAR) doses during adjuvant intensity-modulated radiation therapy (IMRT) for cervical cancer. METHODS: From January 2011 to October 2012, patients undergoing IMRT were included. CT simulation was carried out after inserting vault markers. Planning target volume (PTV)_EBFB received 50 Gy per 25 fractions. Pre-treatment megavoltage CT (MVCT) was performed. MVCTs were registered using bony landmarks with Day 1 MVCT. Displacement of the centre of mass of markers was measured along each axis. Directional ITV was calculated using mean ± 2 standard deviations (SDs) (ITV_study). Replanning was performed using PTV study, and OAR doses were compared with PTV_EBFB using Wilcoxon test. RESULTS: A total of 348/386 data sets were evaluable for 16 patients. The median vaginal displacement was 1.2 mm (SD, 1.3 mm), 4.0 mm (SD, 3.5 mm) and 2.8 mm (SD, 3.3 mm) in the mediolateral, superoinferior and anteroposterior directions, respectively. The ITV margins were 4.1, 10.3 and 10.6 mm. ITV_study and ITV_EBFB were 115.2 cm(3) (87.7-152.2 cm(3)) and 151 cm(3) (95.7-277.1 cm(3)) (p < 0.0001), respectively. PTV_study and PTV_EBFB were 814 and 881 cm(3) (p < 0.0001), respectively. Median doses to the bladder were lower with the PTV_study (46.2 Gy vs 43.2 Gy; p = 0.0001), and a similar trend was observed in the volume of the small bowel receiving 40 Gy (68.2 vs 60.1 cm(3); p = 0.09). CONCLUSION: Population-based PTV margins can lead to reduction in OAR doses. ADVANCES IN KNOWLEDGE: Population-based ITV may reduce OAR doses while executing adjuvant IMRT for cervical cancer.
Subject(s)
Radiotherapy, Intensity-Modulated/methods , Uterine Cervical Neoplasms/radiotherapy , Vagina/radiation effects , Dose Fractionation, Radiation , Female , Humans , Hysterectomy , Male , Middle Aged , Prospective Studies , Radiography, Interventional , Radiotherapy, Adjuvant , Radiotherapy, High-Energy , Urinary Bladder/diagnostic imaging , Uterine Cervical Neoplasms/surgeryABSTRACT
Mast cells are granule-containing cells in mucosal and connective tissues that are known to play a central role in allergic and inflammatory responses owing to pro-inflammatory mediators. Cysts in jaws are among the most common expansive, benign and destructive bone lesions; at some stage they are associated with chronic inflammation. Earlier studies have identified mast cells in odontogenic cysts (OC). We investigated the presence and distribution of mast cells and compared their number in different types of radicular cysts (RC), dentigerous cysts (DC) and odontogenic keratocysts (OKC). Ten cases each of RC, DC and OKC diagnosed clinically and histopathologically were selected and stained with 1% toluidine blue. The greatest number of mast cells/mm(2) was found in RC. The fewest mast cells/mm(2) were found in OKC. The subepithelial zones of all cysts contained more mast cells than the deeper zones.
