Polarization of Tumor Milieu: Therapeutic Implications

Abstract

During neoplastic progression, cancer cells recruit inflammatory cells (monocytes, neutrophils, mast, and dendritic cells, etc.), which become “educated” under the influence of factors released by cancer cells (mainly cytokines). As a consequence, the former lose their ability to present antigens. Instead, they become cells involved in remodeling of extracellular matrix and stimulate the formation of blood vessels (angiogenesis). Proangiogenic factors released by inflammatory cells act as immunosuppressants and the tumor milieu becomes proangiogenic and immunosuppressive. Latest studies have demonstrated the possibility of reverting such proangiogenic/immunosuppressive microenvironment which inhibits tumor growth. Reverted tumor microenvironment becomes anti-angiogenic and immunostimulatory. Reversal of tumor microenvironment is especially feasible with combinations of anti-angiogenic and immunomodulatory factors. For instance, combinations of VEGF, VEGFR2, or TGF-β activity inhibitors with immunostimulants such as anticancer vaccines, CpG sequences, or IL-12 were effective in inhibiting growth of experimental tumors. In our hands, a DNA vaccine directed against endoglin (CD105), a tumor vascular endothelial cell-surface protein, when combined with IL-12, led to a ca. 30 % cure rate in mice bearing experimental melanoma tumors. It appears that attempts to therapeutically revert tumor microenvironment might merit further consideration.