Abstract
Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy.
Highlights
Tumor microenvironment participates in two strictly related processes crucial for tumor progression: formation of tumor blood vessels and presence of immunosuppression milieu, which enables cancer cells to escape from immune surveillance (Huang et al 2013; Szala et al 2010)
The peptide (FITC-CAMEL staining) does not cause the destruction of cell membranes and localizes in the cytoplasm
Our results show that the tumor cell-based vaccine, when used in combination with IL-12 gene therapy, does induce immune response and changes/polarizes the tumor microenvironment from a proangiogenic/immunosuppressive towards an antiangiogenic/immunostimulatory one (Fig. 6)
Summary
Tumor microenvironment participates in two strictly related processes crucial for tumor progression: formation of tumor blood vessels and presence of immunosuppression milieu, which enables cancer cells to escape from immune surveillance (Huang et al 2013; Szala et al 2010). Tumor microenvironment is regulated by numerous factors and processes (Hanahan and Coussens 2012; Swartz et al 2012), as well as by immune system cells (e.g. T lymphocytes, dendritic cells (DCs), NK cells, or macrophages) (Ostrand-Rosenberg 2008; Shurin et al 2012) These cells stimulate tumor growth by releasing proangiogenic and immunosuppressive factors (Tartour et al 2011). Certain drugs [e.g., anti-VEGFR2 monoclonal antibody (Li et al 2006), sunitinib (OzaoChoy et al 2009)] destroy tumor blood vessels and trigger immune response by increasing the levels of CD4? and
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