Tumor immunotherapy has become the fourth major type of cancer therapy, being used alone or in combination with surgery, radiotherapy or chemotherapy. In recent years, immunotherapies, especially immune checkpoint blo...Tumor immunotherapy has become the fourth major type of cancer therapy, being used alone or in combination with surgery, radiotherapy or chemotherapy. In recent years, immunotherapies, especially immune checkpoint blockade (ICB) therapy and chimeric antigen receptor T-Cell (CAR-T), have achieved surprising curative effects in both preclinical studies and clinical practice. However, with the expansion of clinical cases and tumor types treated, the limitations of immunotherapy have gradually emerged. For example, the clinical positive response rate of ICB therapy is only 20%-30%, and is ineffective against or may even promote the progression and metastasis of certain types of tumors. CAR-T cells therapy is very effective against hematological tumors, but its application for treating solid tumors has encountered a bottleneck. Therefore, combination therapeutic strategies have emerged to overcome the drawbacks associated with the different treatments. At present, research on immunotherapy combined with radiotherapy, chemotherapy and targeted therapy is booming. Investigations about the metabolism of tumors and immune cells have become one of the hotspots in recent years. Regulating the metabolism of effector T cells in the tumor microenvironment represents an effective way to improve immunotherapy, resulting in the restoration or enhancement of the ability of effector T cells to produce an anti-tumor immune response. In this review, we discuss recent progress in this field, with an emphasis on the metabolic characteristics of tumor and immune cells, especially T cells in the tumor microenvironment. We also provide a snapshot of how T cell metabolic reprogramming can be regulated to restore or enhance the efficacy of tumor immunotherapy, as well as the challenges and solutions associated with this metabolic reprogramming.展开更多
Kupffer cells,tissue-resident macrophage lineage cell,are enriched in vertebrate liver.The mouse F4/80^+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function:CD68^+ s...Kupffer cells,tissue-resident macrophage lineage cell,are enriched in vertebrate liver.The mouse F4/80^+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function:CD68^+ subpopulation with potent reactive oxygen species(ROS) production and phagocytic capacities,and CD11b^+ subpopulation with a potent capacity to produce T helper 1 cytokines.In addition,CD11b^+ Kupffer cells/macrophages may be migrated from the bone marrow or spleen,especially in inflammatory conditions of the liver.For analyzing diverse Kupffer cell subsets,we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells.During L.monocytogenes infection,hepatic CD69^+ Kupffer cells were significantly induced and expanded,and CD69^+ Kupffer cells expressed higher level of CD11 b,and particularly high level of membrane-bound TGF-β1(mTGF-β1) but lower level of F4/80.We also found that clodronate liposome administration did not eliminate hepatic CD69^+ Kupffer cell subset.We consider the hepatic CD69^+ Kupffer cell population corresponds to CD11b^+Kupffer cells,the bone marrow-derived population.Hepatic CD69^+ Kupffer cells suppressed Ag-nonspecific and OVA-specific CD4 T cell proliferation through mTGF-β1 both in vitro and in vivo,meanwhile,they did not interfere with activation of CD4 T cells.Thus,we have identified a new subset of inflammation-induced CD69^+ Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-β1 at the late stage of immune response against infection.CD69^+ Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response.展开更多
The immune system functions in the organ/tissue of the body.The immune cell differentiation and function are influenced by the organ/tissue microenvironments in which they reside,and the interaction of immune cells wi...The immune system functions in the organ/tissue of the body.The immune cell differentiation and function are influenced by the organ/tissue microenvironments in which they reside,and the interaction of immune cells with the organ/tissue microenvironments may affect and even determine the outcome of the immune responses(Hu and Pasare,2013;Zajac and Harrington,2014).It has been展开更多
基金grants from the National Key Research Program of China (2014CB542102)the National Natural Science Foundation of China (31770966, 31570869).
文摘Tumor immunotherapy has become the fourth major type of cancer therapy, being used alone or in combination with surgery, radiotherapy or chemotherapy. In recent years, immunotherapies, especially immune checkpoint blockade (ICB) therapy and chimeric antigen receptor T-Cell (CAR-T), have achieved surprising curative effects in both preclinical studies and clinical practice. However, with the expansion of clinical cases and tumor types treated, the limitations of immunotherapy have gradually emerged. For example, the clinical positive response rate of ICB therapy is only 20%-30%, and is ineffective against or may even promote the progression and metastasis of certain types of tumors. CAR-T cells therapy is very effective against hematological tumors, but its application for treating solid tumors has encountered a bottleneck. Therefore, combination therapeutic strategies have emerged to overcome the drawbacks associated with the different treatments. At present, research on immunotherapy combined with radiotherapy, chemotherapy and targeted therapy is booming. Investigations about the metabolism of tumors and immune cells have become one of the hotspots in recent years. Regulating the metabolism of effector T cells in the tumor microenvironment represents an effective way to improve immunotherapy, resulting in the restoration or enhancement of the ability of effector T cells to produce an anti-tumor immune response. In this review, we discuss recent progress in this field, with an emphasis on the metabolic characteristics of tumor and immune cells, especially T cells in the tumor microenvironment. We also provide a snapshot of how T cell metabolic reprogramming can be regulated to restore or enhance the efficacy of tumor immunotherapy, as well as the challenges and solutions associated with this metabolic reprogramming.
基金This work was supported by grants from the National Key Basic Research Program of China （2010CB911903 and 2013CB530502）, the National Natural Science Foundation of China （81172851, 81222039, 31270944, and 31370902）, and the National High Technology Research and Development Program （2012AA020900）. We thank Dr. Xingguang Liu for helpful discussion and assistance with manuscript writing, and Ms. Mei Jin and Ms. Hao Shen for their excellent technical assistance.
基金supported by the National Natural Science Foundation of China(91542204,81622023)National Key Basic Research Program of China(2015CB964403,2013CB530502)
文摘Kupffer cells,tissue-resident macrophage lineage cell,are enriched in vertebrate liver.The mouse F4/80^+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function:CD68^+ subpopulation with potent reactive oxygen species(ROS) production and phagocytic capacities,and CD11b^+ subpopulation with a potent capacity to produce T helper 1 cytokines.In addition,CD11b^+ Kupffer cells/macrophages may be migrated from the bone marrow or spleen,especially in inflammatory conditions of the liver.For analyzing diverse Kupffer cell subsets,we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells.During L.monocytogenes infection,hepatic CD69^+ Kupffer cells were significantly induced and expanded,and CD69^+ Kupffer cells expressed higher level of CD11 b,and particularly high level of membrane-bound TGF-β1(mTGF-β1) but lower level of F4/80.We also found that clodronate liposome administration did not eliminate hepatic CD69^+ Kupffer cell subset.We consider the hepatic CD69^+ Kupffer cell population corresponds to CD11b^+Kupffer cells,the bone marrow-derived population.Hepatic CD69^+ Kupffer cells suppressed Ag-nonspecific and OVA-specific CD4 T cell proliferation through mTGF-β1 both in vitro and in vivo,meanwhile,they did not interfere with activation of CD4 T cells.Thus,we have identified a new subset of inflammation-induced CD69^+ Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-β1 at the late stage of immune response against infection.CD69^+ Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response.
基金We are grateful to Miao Chen, Qiangguo Gao and Yiqi Liu （Second Military Medical University, Shanghai, China） for technical support and offer special thanks to Professor Qing Yi （M.D. Anderson Cancer Center Houston, TX, USA） for helpful guidance in the experiments. We thank Shizuo Akira （Osaka University, Osaka, Japan） for originally providing key mouse strains. This work was supported by grants of the National Natural Science Foundation of China （no. 30772502 and 30973455）, Zhejiang Major Medical and the Health Science and Technology ＆ Ministry of Health of the Chinese Government （no. WKJ2009-2-022）. This work was also supported by the Major Research Plan of the Chinese National Natural Science Foundation （no. 91029740）, Zhejiang Province Science and Technology Department Foundation （no. 2009C03012-2） and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents.
基金This work was supported by grants from the National Key Basic Research Program of China （2010CB529901 and 2010CB530600）, the National Natural Science Foundation of China （31100619 and 30972705）, the China Postdoctoral Science Foundation （20110490186）, the Chen-guang Plan Project of Shanghai Educational Municipal Education Commission （11CG48 and szyl0004）, the Specialized Research Fund for the Doctoral Program of Higher Education （20113107120014） and the Leading Academic Discipline Project of Shanghai Municipal Education Commission （J50301） （Yuejuan Zheng, Shanghai University of T.C.M）.
文摘The immune system functions in the organ/tissue of the body.The immune cell differentiation and function are influenced by the organ/tissue microenvironments in which they reside,and the interaction of immune cells with the organ/tissue microenvironments may affect and even determine the outcome of the immune responses(Hu and Pasare,2013;Zajac and Harrington,2014).It has been
