Rôle du TGF-β dans la modulation du microenvironnement tumoral leucémique
The cells and signal molecules (cytokines and chemokines) making up the tumoral microenvironnement are known to play an essential role in tumor progression. It seems to be  necessary to study the relationship between infiltrating cells, tumor cells and signal molecules. TGF-β is a potent immunosuppressive and growth suppressive cytokine whose role in the formation of the leukemia microenvironnement remains unclear. In this study, we investigated the injectable T lymphocyte leukemia EL4 model (tumor cells producing TGF-β) of C57BL/6 strain. We characterised the myeloid and lymphoid infiltration in EL4 tumors using flow cytometry and fluorescence microscopy. Our analysis of EL4 tumor infiltrating cells showed a high concentration of T lymphocytes and myeloid cells CD11b+. We have undertaken our study to better characterize these cells. We showed that these cells are present at the periphery of the tumor and are surrounding blood vessels in the tumor. These cells have phenotypes leading us to believe that they belong to the family of so-called myeloid suppressor cells. They have high levels of transcripts of VEGF and MMP9 in the tumor and the systemic level, but do not seem to have a strong inhibitory capacity in vitro. To determine whether the tumor production of TGF-β affects the recruitment of these cells, we transformed EL4 cells using a shRNA to reduce the production of TGF-β (TGF-β shRNA ) and compared the myeloid and lymphoid infiltration of tumors formed with EL4 cell controls ( shRNA-Luc ) . A 50% decrease in transcript levels of TGF-β does not affect tumor growth but appears to decrease infiltration by myeloid cells. This study allowed us to better understand the pattern of EL4 leukemia and the role of myeloid leukemia cell populations in the tumor microenvironment. The decrease of TGF-β produced by tumor cells reduces the infiltration of these myeloid populations within the EL4 tumor. The precise role of these cells still needs to be determined. These results are in agreement with the fact that anti-TGF-β therapy is not sufficient to counteract tumor progression, but may affect the post-chemotherapy and immunotherapy results by altering the composition of the microenvironment.
Cancer TGF-beta Immunosuppression MDSCs Leukemia Tumor microenvironment