The Activation Mechanism Of Macrophages And Mast Cells In Tumor Microenvironment

The tumor growth is regulated by a precise balance between pro-and anti-tumorigenic effects, stimulated by the tumor cells themselves and their microenvironment. The role of the tumor microenvironment during the study of carcinogenesis is now realized to be important. There is a growing acceptance that bone marrow-derived myeloid cells infiltrating into the tumor microenvironment, including macrophages and mast cells, can play an important role in tumor growth. But the true role of them in tumor remains to be elucidated. This study aims to reveal the effect of macrophages or mast cells on tumor growth. This experiment is subdivided into four parts:Partâ… ,â…¡Effect of macrophages on tumor growth. To observe the effect of Gr-1+CDllb+F4/80+ BMDMs on tumor growth, Gr-1+CDllb+F4/80+ BMDMs prepared from bone marrow cells of naive mice were co-inoculated with H22 cells (co), or injected into palpable tumor (in). The coinoculation of BMDMs with tumor cells suppressed tumor growth, whereas the injection of BMDMs into palpable tumor promoted the growth of tumor. Tumor growth could be significantly promoted by continuous i.p. injection of NTC-Ms starting 10d before tumor inoculation. F4/80+ myeloid cells induced by continuous i.p. injection of NTC-Ms reduced the T cell proliferation. The effect of sTLR4 on tumor growth was observed. In palpable tumor, sTLR4 decreased the transcription of Argl gene and increased the transcription of the IL-12 gene. And sTLR4 significantly suppressed the growth of tumors. F4/80+ cells in tumor immunotherapy microenvironment were mainly Gr-1+CDllb+. The sTLR4 increased transcription levels of Nos2 and IL-12 relative to those of Argl and IL-10 in F4/80+cells in the microenvironment of tumor immunotherapy, further reduced the apoptosis inducing capacity of F4/80+ cells and enhanced the suppressive effect of 4-BBL/sPD-1 on tumor growth.Partâ…¢,â…£Effect of mast cells on tumor growth. To observe the effect of mast cells on tumor growth, BMMCs prepared from bone marrow cells of naive mice were co-inoculated with H22 cells (co), or injected into palpable tumor (in). The coinoculation of BMMCs with tumor cells suppressed tumor growth, whereas the injection of BMMCs into palpable tumor promoted the growth of tumor. In co-inoculation test, the suppress effect of BMMCs on tumor growth was attenuated by SCF, and BMMCs pre-treated with NTC-Ms or TI-Ms promoted tumor growth, which can be suppressed by resveratrol or QNZ. Functional SCF in NTC-Ms or TI-Ms were detected. In intra-tumor injection test, sTLR4 reduced tumor-promoting effect of BMMCs. NTC-Ms, TI-Ms or SCF/LPS could suppress spontaneous degranulation of mast cells but not secretion of VEGF and PDGF. And SCF/LPS, NTC-Ms or TI-Ms treatment increased the expression of IL-10 in BMMCs, but resveratrol, wortmannin or QNZ suppressed the effect of SCF/LPS, NTC-Ms and TI-Ms on BMMCs. Inhibition effect of SCF/LPS, NTC-Ms or TI-Ms on BMMCs degranulation were eliminated by LiCl. IL-10 expression in BMMCs was suppressed by LiCl. Tumor growth could be suppressed if mice received i.p. injection of LiCl. In co-inoculation test, when BMMCs were pre-treated with LiCl,.the percentage of CD8+ T cells in tumor increased, IL-10 expression in the tissues at inoculation sites decreased, tumor growth were suppressed.In summary, we investigate the influence of tumor microenvironment on macrophages and mast cells, and explore the mechanism of functional switch. This study would provide scientific rational for the next step of target immune therapy.