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Priming stroma with a vitamin D analog to optimize viroimmunotherapy for pancreatic cancer.

ABSTRACT: Pancreatic cancer resistance to immunotherapies is partly due to deficits in tumor-infiltrating immune cells and stromal density. Combination therapies that modify stroma and recruit immune cells are needed. Vitamin D analogs such as calcipotriol (Cal) decrease fibrosis in pancreas stroma, thus allowing increased chemotherapy delivery. OVs infect, replicate in, and kill cancer cells and recruit immune cells to immunodeficient microenvironments. We investigated whether stromal modification with Cal would enhance oncolytic viroimmunotherapy using recombinant orthopoxvirus, CF33. We assessed effect of Cal on CF33 replication using pancreas ductal adenocarcinoma (PDAC) cell lines and in vivo flank orthotopic models. Proliferation assays showed that Cal did not alter viral replication. Less replication was seen in cell lines whose division was slowed by Cal, but this appeared proportional to cell proliferation. Three-dimensional in vitro models demonstrated decreased myofibroblast integrity after Cal treatment. Cal increased vascular lumen size and immune cell infiltration in subcutaneous models of PDAC and increased viral delivery and replication. Cal plus serial OV dosing in the syngeneic Pan02 model caused more significant tumor abrogation than other treatments. Cal-treated tumors had less dense fibrosis, enhanced immune cell infiltration, and decreased T cell exhaustion. Calcipotriol is a possible adjunct for CF33-based oncolytic viroimmunotherapy against PDAC.

SUBMITTER: Kim SI

PROVIDER: S-EPMC8914466 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Priming stroma with a vitamin D analog to optimize viroimmunotherapy for pancreatic cancer.

Kim Sang-In SI Chaurasiya Shyambabu S Sivanandam Venkatesh V Kang Seonah S Park Anthony K AK Lu Jianming J Yang Annie A Zhang Zhifang Z Bagdasarian Isabella A IA Woo Yanghee Y Morgan Joshua T JT Yin Zhirong Z Fong Yuman Y Warner Susanne G SG

Molecular therapy oncolytics 20220222

Pancreatic cancer resistance to immunotherapies is partly due to deficits in tumor-infiltrating immune cells and stromal density. Combination therapies that modify stroma and recruit immune cells are needed. Vitamin D analogs such as calcipotriol (Cal) decrease fibrosis in pancreas stroma, thus allowing increased chemotherapy delivery. OVs infect, replicate in, and kill cancer cells and recruit immune cells to immunodeficient microenvironments. We investigated whether stromal modification with C ...[more]

PMID: 35317522

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Project description:BackgroundSeed germination and seedling growth constitute the first stage of a plant's life cycle for crop establishment. Arthrocnemum Moq. is a halophyte of the subfamily Salicornioideae (Amaranthaceae), which could be recognized in the foreseeable future as an emerging candidate in applied biosaline agricultural programs, mainly due to the large biomass it represents in coastal and inland saltmarshes, in addition to its interesting nutritional and pharmacological properties. However, to ensure their subsequent use as a crop, it is necessary to optimize their germination through appropriate seed priming treatments. The main goal of this work was to seek the optimization of Arthrocnemum germination process using different pretreatments: exposure to sodium chloride (100 to 1200 mM) in the dark and its subsequent transferred to distilled water separately and together with the combination of pH (5, 7, 9), salinity (0, 100, 200 mM NaCl), and iron conditions (0, 200, 400 µM FeSO4). The experiments were tested on six samples of two different species: A. meridionale (from Tunisia) and A. macrostachyum (from Spain).ResultsSalinity priming of seeds for 15 days in darkness improved germination percentages by almost 25% at 600 mM NaCl, in both Tunisian and Spanish species. However, keeping seeds at different salt concentrations for 30 days produced higher improvement percentages at lower concentrations in A. meridionale (100-200 mM NaCl), while in A. macrostachyum the highest improvement percentages were obtained at 600 mM NaCl (percentage improvement of 47%). When the dark time period is reduced to 5 days at higher salt concentrations, the greater germination percentages were reached in all the samples at the concentration of 800 mM NaCl, increasing the improvement of germination between 17 and 50%. Finally, the conditions of pH = 7, pretreatment in darkness at 800 mM NaCl and 400 µM or iron, turned out to be an effective medium for seed germination.ConclusionsTherefore, before using Arthrocnemum seeds in applied biotechnological programs, a seed priming treatment based on prior exposure to high salt concentrations (600-1000 mM NaCl) is recommended in order to maximize germination percentages.

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Priming stroma with a vitamin D analog to optimize viroimmunotherapy for pancreatic cancer.

Publications

Priming stroma with a vitamin D analog to optimize viroimmunotherapy for pancreatic cancer.

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