Synergistic effects of AAGL and anti-PD-1 on hepatocellular carcinoma through lymphocyte recruitment to the liver
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Abstract:
Objective: Therapy for hepatocellular carcinoma (HCC) is a major challenge, and targeted therapies provide only a modest benefitin terms of overall survival. Treatment with antibodies to programmed cell death protein 1 (PD-1)/PD-L1 can restore the functionsof tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20% of patients with advanced HCC. Novel approaches areurgently needed to treat HCC and to augment the efficacy of immunotherapy. Methods: Tumor-bearing mice were treated with Agrocybe aegerita galectin (AAGL) alone or in combination with anti-PD-1, and thetumor sizes and lifespans of mice were determined. Transcriptome analysis, cytokine analysis, flow cytometry analysis of the numberand proportion of immune cell subsets in the liver and spleen, and molecular and cellular analyses of tumors were used to define theunderlying mechanisms. Results: AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner. Furthermore, AAGL increased theexpression of multiple cytokines and chemokines in tumor-bearing mouse livers; this effect was associated with the activation andmigration of T cells and macrophages, in agreement with the in vitro results. Importantly, the aggregation of T cells and macrophagesinduced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy. Conclusions: The results showed that AAGL induced the activation and migration of lymphocytes to the liver, and that thecombination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.Keywords:
Liver Cancer
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The initiation and progression of liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are dependent on its tumor microenvironment. Immune cells are key players in the liver cancer microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells are closely related to cell metabolism. However, the effects of metabolic changes of immune cells on liver cancer progression are largely undefined. In this review, we summarize the recent findings of immunometabolism and relate these findings to liver cancer progression. We also explore the translation of the understanding of immunometabolism for clinical use.
Liver Cancer
Tumor progression
Crosstalk
Cancer-Associated Fibroblasts
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Objective The aim of this study was to investigate the pathomorphological changes of spleen lymphocyte apoptosis after 60 Co γ-irradiation. Methods The mice were irradiated with 6,9,12,15 and 20 Gy of 60 Co γ-rays. At different times after irradiation,the mice were sacrificed and the pathological changes of spleen lymphocyte were observed by light and transmission electron microscopies. Results Spleen lymphocyte decreased evidently and the peak of apoptosis in spleen lymphocyte was dependent on radiation dose and the time after irradiation. Conclusion After γ-irradiation with large doses,pathological changes of spleen lymphocyte apoptosis in mice can be divided into obviously different stages. The main causes of death of spleen lymphocytes are different in different dose groups.
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Objective:The spleen-deficiency-suffering mice models are observed dynamically on the perspective of pharmacokinetics and by radioactive tracer method,and the effect of spleen-reinforcing therapy on the mice's obsorption of Fe and the process of transporting and distribution is observed as well,so that the relationship between the spleen's function of dominating transporting/ dysfunction of the spleen in transporting and Fe metabolim is researched; The biological meaning of spleen's function of dominating transporting is discussed;The scientific content of the important TCM theories of spleen's dominating the transporting and spleen's determining the condition of the acquired construction is revealed;the experimental basis is provided for the research on spleen's functions and /or the essence of spleen-deficiency syndrome.Method: 80 Male SD mice are divided by random into normal group,normal reinforcing-spleen group,spleen-deficiency group,reinforcing-spleen-deficiency group.The mice model are fed 59 Fe Cl3 and 0.2 ml water-floating fluid at one time;the mice of the groups of normal reinforcing-spleen and reinforcing-spleen-deficiency are fed 1.5ml 1:1 Si Jun Zi Tang;the groups of normal and spleen-deficiency are fed 1.5 ml normal sanile once a day.3 rats of each group will be selected by random at 0.5,1,2,4,8 and 14 phase and are made dead by eyeball blood letting method,and then radio 59 Fe level is measured by Y radio-immunity counter after the organs and tissues of spleen,liver,small intestine,stomach and kidney are extracted,and the pharmacokinetics change of radio Fe's transporting and distribution from the whole body's circulatory system to the rats's tissues and organs.Results: 59 Fe transporting exists significant difference in the condition of spleen-deficiency and reinforcing-spleen,the therapy of reinforcing-spleen improve the transporting and distribution of 59 Fe of the mice.Conclusions: 59 Fe's transporting process from blood circulatory system to the organs and tissues decreased in the condition of spleen-deficiency,the therapy of reinforcing-spleen can promote the transporting of 59 Fe in the tissues and organs of the mice,especially concentrating on the spleen,which shows that Si Jun Zi Tang has the function of regulating the spleen-deficiency by reinforcing the spleen so that the substance transporting system of the organism is regulated.
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Single 1-day-old C3H spleen grafts in adult splenectomised (AKR X C3H)F1 mice grew to a larger size and contained more lymphoid tissue than grafts in sham-operated mice. In splenectomised hosts, individual spleen grafts attained a progressively smaller size in hosts grafted with 6 and 12 spleen grafts per animal. Thus the total mass of spleen graft tissue in such animals reached a plateau which approximated the weight of the normal spleen in such animals. Similar results were obtained with AKR spleen grafts in AKR mice and with C57BL spleen grafts in (AKR X C57BL) F1 hybrid mice. In sham-operated hosts a similar tendency for a reduction in individual spleen graft size after multiple grafting was also noted. Total spleen mass appears to be under positive regulation by the body but the mechanisms involved are unknown.
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Objective:On basement of model of rat' deficient spleen syndrome,these are the dynamic observation studies of?~(59) Fe's obsorbed metabolism and /or transported metabolism course of the rat of deficient spleen syndrome and replenishing spleen method by the application of radioactivity label technology in pharmacokinetics.The experiment studies the relation of the spleen being the transferring owner or the spleen losing the transferring owner with Fe's metabolism,researches it's biology meaning of spleen being the owner of transmission,researches the science intension of important traditional Chinese medicine theory of spleen being the owner of transmission and the spleen serving as basement of the day after tomorrow,and provides the experiment basis of spleen merit ability and/or essece of deficient spleen syndrome.Methods:40 male SD rats were randomly divided into 4 groups:normal group,normal replenishing spleen group,deficient spleen group,deficient spleen-replenishing spleen group.According to the requirement of the animal model standardizes most of rats were made the pattern.4 goups were once iffigated shui xuanye of?~(59) FeCl_3 0.2ml/220g/a rat.At the same time,according to weight of a person and a rat,2 groups of normal replenishing spleen group and deficient spleen-replenishing spleen group were given 1.5m±medicinal ingredients liquid of 1:1 four-man decoction,the others were given 1.5m±physiological saline,once a day.Respectively at 0.5h,1h,1.5h,3h,6h,12h and 24h,blood 0.2ml of all rats were taken from rat's tail,measured its radioactivity?~(59) Fe with γ-radiation immunity counter,to observe changes of pharmacokinetics of?~(59) Fe passing through rat's stomach and bowel way into the whole body blood-system.Results:The experiment exists the clear difference for changes of radioactivity?~(59) Fe pharmacokinetics in the states of deficient spleen and replenishing spleen to absorb?~(59) FeCl_3 from rat's stomach and bowel way into the whole body blood-system.Replenishing spleen method have promoted the absorb to?~(59) FeCl_3.Conclusions:The rat of deficient spleen syndrome has reduced the bioavailability of?~(59) FeCl_3 and made it the lower lever to absorb of?~(59) FeCl_3.On the contrary,Replenishing spleen method has promoted to absorb?~(59)(FeCl_3).from rat's stomach and bowel way into the whole body blood-system.
Decoction
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Objective To observe and explore the effect of activating the spleen for the immune function of spleen deficiency rat.Methods The priscription of Yunpi is composed of Huangqi,Danggui,Cangzhu,Longgu and so on.Reserpine was used to duplicate spleen deficiency model.We divided the rats into three groups:normal grouop,model group and therapy group to observe the effect of activating the spleen for the tissue structure of main immune organ such as spleen and thymus,serum IgG,IgA,IgM,SOD.Results Activating the spleen could significant repair the tissue structure of thymus and improve Ig,SOD.Conclusion Activating the spleen could significant improve immune function of spleen deficiency rat by improving SOD,Ig and repairing the tissue structure of thymus.
Reserpine
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Neoplasm
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The experiment was conducted to evaluate the effect of Aspirin on animal immune function by studying the effects of different doses of Aspirin on the lymphocyte activity in mice blood and spleen. Forty eight Kunming mice (20±2g) were selected and assigned randomly to 4 groups to finish the experiment. The treatment contained low-dose (10mg/k g·bw), middle-dose (20 mg/k g·bw), high-dose (40 mg/k g·bw) Aspirin group and blank control group. T he experimental stage was 20 days. On the 10 th and 20 th day in the trial, 6 mice were chosen randomly to be sampled and the indexes were determined. The activity of lymphocyte in low and middle dos e groups were enhanced and the activity of lymphocyte in middle dos e group was higher than that in low dos e group, but there was no significant difference (p>0.05). On the 20 th day in the trial, the activity of lymphocyte in spleen in middle dose group was significantly higher than that in control group (p<0.05). On the 20 th day in the trial, the activity of lymphocyte in spleen in middle dose group was significantly higher than that in control group (p<0.05). During the course of the trial, during the course of the trial, the activity of lymphocyte in blood and spleen in high dose group de creased, but there was no the activity of lymphocyte in blood and spleen in high dose group decreased, but there was no significant difference (p>0.05). This indicated that proper dose of Aspirin could enhance the activity of lymphocyte in mice significant difference (p>0.05). This indicated that proper dose of Aspirin could enhance the activity of lymphocyte in mice.
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