Synergetic Effect Of IL-15 And IL-18 Can Enhance Function Of Tumor-infiltrating Lymphocytes In Colon Cancer

Background. The tumor-infiltrating lymphocytes (TILs) are a heterogeneous lymphocyte populations, majority of which is T cells and contains a small amout of B cells and NK cells, in the tumor stroma. They infiltrate into tumor and play a role in anti-tumor. It's general considered that the immune system in patients with malignant tumors is in tolerance of local and systemic or defect state, studies have shown that stimulation of TIL in vitro are more likely differential to TH1 cells, while the killing activity was not significantly increased. It seems that some substances may inhibite the killing function of tumor-infilitrating lymphocytes in the tumor microenvironment.Colorectal cancer is the most common gastrointestinal cancer, according to statistics, the death rate of colorectal cancer accounted for about 10% of total mortality in the United States. It caused about 20 million people die in China each year, and caused disease control departments and clinicians highly valued. The treatment of colon cancer is radical surgery based on comprehensive cancer treatment, has obvious limitations because of side effects. Therefore, it emergency for searching low toxicity anticancer drugs.Cytokine imbalance is considered to be one of necessary conditions of malignant tumor growth, invasion and metastasis. In recent years, more and more researches focus on the relationship between cytokines and cancer, such as TNF family, IL family, GF family and IFN family.Interleukin 15(IL-15) discovered in 1994 has similar biology activity of IL-2, which can promote the proliferation and anti-tumor activity of NK cells and CTL cells. IL-4 can stimulate the PHA activated peripheral blood T cell proliferation, B cell antibodies secretion and promote NK cell proliferation and cytokine secretion. It plays a important role in anti-tumor immunity response and immune regulation.IL-18, which is an important regulatory factor in innate and cellular immune respons, is a member of IL-1 ligand family. It has a similar biology activity, can strongly induce secretion of IFN-y. IL-18 can promote T cell, NK cell proliferation and secrete IFN-y, enhance cell-mediated cytotoxicity of perforin and FasL. Both of these two cytokines alone can enhance immune function, boost the immune system anti-tumor cells. But rarely reports about their influence of TIL, or wherther synergetic effect of IL-15 and IL-18 can influence the TIL differential to TH1 cells and enhance anti-tumor function.Hypothesis:We suggesting that IL-15, IL-18 may modulate cytokine secretion of TIL, perform a killing effect against the tumor cells. We focus on which type of cytokines are stimulated, the killing activity of TIL and tumor metastasis, macrophage phagocytosis.Methods. In the present study, IL-15 and IL-18 co-stimulated TIL from cancer of colon patients and evaluated the function of TIL by detecting TGF-β, IL-4, IFN-y and cytotoxicity of TIL in vitro. IL-15 and IL-18 co-stimulated TIL from cancer of colon patients, then SW480 cells were inoculated with TIL and feed into SCID mice, estabilish human colon cancer bearing mouse model. We evaluated the function of TIL by detecting size of tumor on SCID mice, tumor metastasis of liver, IL-4, IFN-y in serum and the swallow ability of the mouse peritoneal macrophagesResults. In the present study, synergetic effect of IL-15 and IL-18 can inhibit the secretion of TGF-βand IL-4 from TIL in vitro, increase the secretion of T IFN-y from TIL,meanwhile can enhance the cytotoxicity of TIL.Synergetic effect of IL-15 and IL-18 can inhibit the secretion of TGF-βand IL-4 from TIL, increase the secretion of T IFN-y from TIL, meanwhile can enhance the cytotoxicity of TIL. At mean while, can extend survival time and inhibit tumor growth significantly, inhibit the tumor metastasis of liver, enhance the swallow ability of the mouse peritoneal macrophages cells and increase the expression of IFN-y and decrease the IL-4 expression in vivo.Conclusions. Synergetic effect of IL-15 and IL-18 can activated tumor-infiltrating lymphocytes in vivo and in vitro.