Study of modulation of the myeloid-derived suppressor cells metastatic adenocarcinoma after anti-angiogenic therapy

Abstract

Renal cell carcinoma (RCC) represents approximately 2-3% of malignant tumors in humans is the most aggressive of urologic cancers. The most frequent subtype of RCC is clear cell (ccRCC). Most patients have mutations in tumor suppressor gene von Hippel-Lindau (VHL) which results in increased transcription of various angiogenic factors such as the vascular endothelial growth factor (VEGF). In addition to angiogenic activity, VEGF may adversely affect the tumor adaptive immune response. In RCC patients, increased levels of VEGF has been associated with changes in the differentiation of myeloid cells. For metastatic RCC (mRCC) the first-line drugs are inhibitors of angiogenic and despite the relative success of these drugs, many patients have disease progression which shows an adaptive response of these tumors. Among other causes, myeloid suppressor cells seem to favor this adaptive response. The endostatin (ES) is the product of cleavage of the carboxy-terminus of collagen XVIII. ES inhibits proliferation, migration and stimulates apoptosis of endothelial cells and numerous studies have proven effective in the treatment of various tumor types. Gene therapy can be defined as the transfer of genetic material aimed at treating inherited or acquired diseases. Viral vectors, retroviruses in particular has been widely used in clinical trials. Our group has apresentodo promising results with gene therapy with ES both in the treatment of CRC in primary and metastatic RCC (mRCC). In both models, experimental treatment with ES promoted a significant change in the tumor microenvironment. Aside from the reduction of vascular endothelium, we observed a significant increase in the inflammatory response with production of cytokine anti-tumor. However, no animal showed complete remission of tumors. Knowing that the suppressor cells are myeloid populations responsible for an immune-resistant tumor. In this project we intend to evaluate the possible modulation of expansion and suppressive activity of myeloid cells in an animal model of metastatic adenocarcinoma underwent gene therapy with ES.