In this study, we sought out to study the anti-cancer effects of propranolol (Pro) in combination with tumor lysate vaccine on lymphocyte proliferation activities as well as on IL-2, IL-4, IL-10, IL-12, IL-17 and IFN-? cytokine concentration in the tumor microenvironment (TME). A tumor model was established in inbred Balb/C mice using transplantation of tumor to the flank of native mice. Tumor-bearing mice were immunized with lysate tumor cells (vaccine), a combination of Pro/Vaccine (Vac). Control groups consisted of tumor-bearing mice receiving only propranolol or PBS three times with one week interval via subcutaneous (s.c) injection. One week after the last immunization, tumor was removed, homogenate was prepared and the levels of IL-12, IL-17, 1L-2, IL-10, IL-4, IFN-? cytokine concentrations were evaluated by commercial ELISA kits. In addition, spleen cell suspension was used for the lymphocyte proliferation assay using the BrdU method. Results from this study indicated that Pro/Vac had the ability to significantly increase lymphocyte proliferation, and to suppress tumor growth. Administration of breast tumor lysates with propranolol increased the concentration of IL-12, IL-17, 1L-2 and IFN-? cytokines in tumor microenvironment. This study has proved the efficiency of propranolol as an adjuvant in combination with the tumor vaccine model on tumor suppression via cytokine pattern modulation in tumor microenvironment.
Psoriasis is a chronic inflammatory skin disease characterized by a relapsing-remitting disease course and correlated with increased expression of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 22 (IL22). Psoriasis is hard to treat because of the unpredictable and asymptomatic flare-up, which limits handling of skin lesions to symptomatic treatment. Synthetic biology-based gene circuits are uniquely suited for the treatment of diseases with complex dynamics, such as psoriasis, because they can autonomously couple the detection of disease biomarkers with the production of therapeutic proteins. We designed a mammalian cell synthetic cytokine converter that quantifies psoriasis-associated TNF and IL22 levels using serially linked receptor-based synthetic signaling cascades, processes the levels of these proinflammatory cytokines with AND-gate logic, and triggers the corresponding expression of therapeutic levels of the anti-inflammatory/psoriatic cytokines IL4 and IL10, which have been shown to be immunomodulatory in patients. Implants of microencapsulated cytokine converter transgenic designer cells were insensitive to simulated bacterial and viral infections as well as psoriatic-unrelated inflammation. The designer cells specifically prevented the onset of psoriatic flares, stopped acute psoriasis, improved psoriatic skin lesions and restored normal skin-tissue morphology in mice. The antipsoriatic designer cells were equally responsive to blood samples from psoriasis patients, suggesting that the synthetic cytokine converter captures the clinically relevant cytokine range. Implanted designer cells that dynamically interface with the patient's metabolism by detecting specific disease metabolites or biomarkers, processing their blood levels with synthetic circuits in real time, and coordinating immediate production and systemic delivery of protein therapeutics may advance personalized gene- and cell-based therapies.
