Polymer-induced tumor immunotherapy by in situ activation of antigen-presenting cells
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Abstract
Cancer is one of the most common diseases with a global incidence of 20 million people, responsible for 10 million deaths in 2020. The tendency is increasing. Normally, our immune system recognizes mutated cells and eliminates them. Cancer cells, however, are able to develop escape strategies that interfere with their elimination. Cancer immunotherapies aim at reinstalling the inherent capacity of immune cells to recognize and eliminate tumor cells. To induce a tumor-specific immune response able to eliminate cancer cells in the presence of an immunosuppressive tumor microenvironment, we established an immune stimulating and antigen-presenting nanoparticle (NP) platform. The NPs are decorated with ovalbumin (OVA) as model antigen and 1-(4-(aminomethyl)- benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4- amine (IMDQ) as an immune stimulatory TLR7/8 agonist. They are characterized by pH sensitivity, well toleration and safety for intravenous injection.
To analyze the potential of our NPs in vivo, we inoculated B16-F10 or MC38 tumor cells either expressing membranous or cytosolic bound OVA or without expressing the antigen as control subcutaneously in the flank of C57BL/6 wild-type mice. When the tumor was pulpable with a size of about 0,25 mm3 mice were vaccinated intravenously three times (on day 3, 5 and 7) with our nanogel to develop an immune response against our model antigen OVA in a therapeutic setting. Every two days we measured the tumor volume and once a week we took blood from the mice to determine the antibody titer. After approximately two weeks we sacrificed the mice and analyzed the immune responses concerning cytokines, T cell and B cell production. Furthermore, we analyzed the sera, splenocytes and lymphocytes from the mice via flow cytometry. We could show that our NP therapy was able to reduce the tumor growth in two different tumor models. The particles provided an antigen specific tumor immunity by inducing a Th1-mediated immune response and a high production of CD8+ T cells. These results were also confirmed by single cell RNA analysis. Further evaluation and experiments are needed to decipher the differences in the T cell response and the role of the involvement of B cells in combination with T cells in the different models.