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Gemcitabine (GEM) is a commonly used drug in the clinical treatment of non-small cell lung cancer. Due to the accumulation of cells mediating immune escape and T cell depletion after chemotherapy, tumor microenvironment (TME) tends to be immunosuppressive status, which ultimately leads to tumor metastasis. The experimental protocol was approved by the Medical Laboratory Animal Ethics Committee of Jiangsu Provincial Academy of Chinese Medicine. Therefore, we observed the immunomodulatory effects of micro-particulate Ganoderma lucidum spore β-glucan (PGSG) on macrophages in vitro experiments. Next, mice subcutaneous Lewis lung cancer models were established to observe the anti-tumor effects of PGSG through oral administration of PGSG combined with GEM. Flow cytometry analysis was used to analyze the ratio of anti-tumor T cells in tumors and spleen, as well as the proportion of myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM) and regulatory cells (Tregs). The results showed that PGSG can up-regulate the expression of major histocompatibility antigens (MHC-II), CD40, CD86 and CD80 on the surface of macrophages, enhance the ability to phagocytosis of neutral red and further mediate the release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4) and interleukin-10 (IL-10). In vivo experiments, combined administration can significantly decrease the volume and weight of tumors, reduce the ratio of MDSC (CD11b+Gr-1+), M-MDSC (CD11b+Ly6G-Ly6Chigh) and Treg (CD4+Foxp3+). At the same time, PGSG promoted the conversion of M2 (F4/80+CD206+) to M1 (F4/80+MHC-II+) and enhanced the response of helper T cell-1 (Th1) (CD4+IFN-γ+) and cytotoxic T lymphocyte (CTL) (CD8+IFN-γ+), which is of great significance for killing tumors. These results suggest that PGSG can regulate innate and adaptive antitumor immune responses, reshape the immunosuppressive microenvironment and enhance the anti-lung cancer effect of GEM.
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Traditional Chinese medicine attaches great importance to the health Qi in the prevention and treatment of malignant tumors and emphasizes the concept of "harmonizing yin and yang until a balance is reached". Professor Liu Jiaxiang has established an academic system of "strengthening the health Qi to treat cancer" characterized by "putting people first" and "protecting the health Qi", emphasizing the regulation of the body's internal resistance (including immunity) to prevent and treat malignant tumors. The tumor immunotherapy has been proven effective in the field of pan-cancer and is considered as the most possible cure for cancer. This article deeply studies the scientific connotation of "health Qi" of human body and its role in tumor pathogenesis from the perspective of tumor immunology, which will promote the mutual promotion and integration of traditional Chinese medicine and oncology, and further improve the efficiency of prevention and control of malignant tumors in China through the integration of traditional Chinese and Western medicine.
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The complex tumor microenvironment is a most important factor in cancer development. The biological microenvironment is composed of a variety of barriers including the extracellular matrix and associated cells such as endothelia cells, pericytes, and cancer-associated fibroblasts. Different strategies can be utilized to enhance nanoparticle-based drug delivery and distribution into tumor tissues addressing the extracellular matrix or cellular components. In addition to the biological microenvironment, the immunological conditions around the tumor tissue can be very complicated and cancer cells have various ways of evading immune surveillance. Nanoparticle drug delivery systems can enhance cancer immunotherapy by tuning the immunological response and memory of various immune cells such as T cells, B cells, macrophages, and dendritic cells. In this review, the main components in the tumor biological and immunological environment are discussed. The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy.
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In this study, an immunostimulating particulate β-glucan was isolated from a hot alkaline extract of the fruiting bodies of Ganoderma lucidum. The optimum conditions of 8 hours treatment time, 1∶20 solid - liquid ratio and 55 ℃ for the alkaline extract process were obtained after investigating by single-factor experiments and Box-Benhnken design in terms of the Ganoderma lucidum particulate β-glucan (GLG) increment, and these conditions resulted in a GLG yield of 8.57%. The experimental protocol was approved by the Medical Laboratory Animal Ethics Committee of Jiangsu Provincial Academy of Chinese Medicine. The result showed that resident macrophages were effectively activated by GLG, such as with the up-regulation of co-stimulatory molecules, the secretion of cytokines and phagocytic uptake. GLG could also promote the proliferation of spleen lymphocytes in mice. In addition, IFN-γ production of spleen CD4+ T cells and cytotoxic T lymphocyte (CTL) responses were significantly enhanced on GLG orally treatment, which ultimately resulted in significantly decreased tumor burden. Taken together, these data suggest that GLG might act as an immune stimulator to exert antitumor effects.
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Several studies have demonstrated that memory T cells including stem cell memory (Tscm) T cells and central memory (Tcm) T cells show superior persistence and antitumor immunity compared with effector memory T (Tem) cells and effector T (Teff) cells. Furthermore, the Tcm/Teff ratio has been reported to be a predictive biomarker of immune responses against some tumors. Thus, a system-level understanding of the mechanisms underlying the differentiation of effector and memory T cells is of increasing importance for developing immunological strategies against various tumors. This review focuses on recent advances in efficacy against tumors, the origin, formation mechanisms of memory T cells, and the role of the gut microbiota in memory T cell formation. Furthermore, we summarize strategies to generate memory T cells in (ex) vivo that, might be applicable in clinical practice.
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Several studies have demonstrated that memory T cells including stem cell memory (Tscm) T cells and central memory (Tcm) T cells show superior persistence and antitumor immunity compared with effector memory T (Tem) cells and effector T (Teff) cells. Furthermore, the Tcm/Teff ratio has been reported to be a predictive biomarker of immune responses against some tumors. Thus, a system-level understanding of the mechanisms underlying the differentiation of effector and memory T cells is of increasing importance for developing immunological strategies against various tumors. This review focuses on recent advances in efficacy against tumors, the origin, formation mechanisms of memory T cells, and the role of the gut microbiota in memory T cell formation. Furthermore, we summarize strategies to generate memory T cells in (ex) vivo that, might be applicable in clinical practice.
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Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery.
Subject(s)
Animals , Female , Humans , Mice , Carcinoma, Non-Small-Cell Lung , Allergy and Immunology , Therapeutics , Cell Line, Tumor , ErbB Receptors , Allergy and Immunology , Metabolism , Immunotherapy, Adoptive , Methods , Lung Neoplasms , Allergy and Immunology , Therapeutics , Mice, Inbred NOD , Receptors, Chimeric Antigen , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology , Xenograft Model Antitumor AssaysABSTRACT
@#Studies have found that a variety of tumors continue to activate PD-1(programmed cell death protein 1, PD-1)/PD-L1(programmed cell death-ligand 1)signaling pathway by up-regulating PD-L1 expression in tumor cells and microenvironment. The dysfunction of T cells leads to the occurrence of tumor immune escape. Several PD-1/PD-L1 monoclonal antibodies have been marketed to achieve significant clinical efficacy. However, because of the high production cost, the harsh conditions for storage and transportation, and the potential immunogenicity of monoclonal antibody, the seeking for PD-1/PD-L1 small molecule inhibitors has become a hot spot in the development of new drugs. In this paper, the biological mechanisms of PD-1/PD-L1 was introduced in detail. Based on the structural classification, the research progress of PD-1/PD-L1 small molecule inhibitors was reviewed, with a prospect of the development of small molecule inhibitors.
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This short article is dedicated to the 90th Anniversary of the School of Life Sciences at Zhejiang University, China. Immunotherapy of cancer is currently a hot topic in the biomedical field, and a re-search focus of my laboratory is on developing new and effective combinatorial immunotherapeutic strategies for liver cancer. Of note, my interest in immunotherapy of cancer stems from the training as an undergraduate student at Hangzhou University, China, almost 40 years ago.
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The occurrence and development of tumors are closely related to the tumor microenvironment. Among them, tumor immune microenvironment and tumor metabolic microenvironment play important roles in tumor. Tumor immunotherapy is a way to kill tumor cells by activating the body's immune system. Tumor immunotherapy has shown good therapeutic effects in a variety of solid tumors. In recent years, significant progress has been made in tumor immunotherapy. The Warburg effect indicates that tumor cells use aerobic glycolysis to acquire energy. In the tumor, the energy metabolism pathway is abnormal, and the tumor microenvironment can induce the reprogramming of tumor cell metabolism. Therefore, targeting tumor metabolism is also of great significance for tumor treatment. In this paper, we reviewed the research progress of drug targets related to tumor immunology and tumor metabolism in recent years, as well as the progress of drug development.
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Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme in the human tryptophan metabolism pathway, which can mediate tumor immune response. An IDO1 inhibitor would be a potential cancer immunotherapy drug. Based on the recently reported crystal of an IDO1 protein-inhibitor complex (PDBID: 6AZV), the structure of reported inhibitor, and by analyzing the interaction mode between the inhibitor and IDO1, new inhibitor molecules were designed and synthesized. All structures were confirmed by spectral data. Preliminary activity studies showed that compounds containing an azabiphenyl tetrazole structure (B1 and B2) and biphenyl compounds containing a sulfonamide structure (D1, D2 and D3) had excellent inhibitory activity of IDO1 at the enzyme and cell level, and were comparable or even better than the control drug INCB24360.
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In recent years, the studies have found that the intestinal micro-ecology is closely related to the development and treatment of tumors. This article aims to summarize the advance of anti-tumor mechanism of metformin through regulation of gut microbiota, describe the problems and its prospect in the research process.
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Cancer-associated inflammation is one of the key features of cancer. Many cytokines are involved in inflammation and its regulation and play important roles in many factors affecting tumor biology. Inflammation participates in the construction of tumor mi-croenvironments (TMEs) by changing the homeostasis of tumor tissues. The interaction of cytokines secreted by TME-infiltrating cells forms a complex network of cytokines that play a role in tumor progression through various mechanisms such as inflammation promo-tion, immune editing, and immune escape. This review aims at analyzing the research progress on the relationship between inflamma-tion, cytokine networks, and TMEs
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Neutrophils in the tumor microenvironment have anti-tumorigenic (N1) or pro-tumor igenic (N2) functions.N1 neutrophils are manipulated to have cytotoxicity against tumors;N2 neutrophils can lead to the tumorigenesis,tumor growth,metastasis and tumor angiogenesis by secreting neutrophil elastase,matrix metalloproteinases,cytokines and chemokines.This review summarizes the biological characteristics of N1 and N2 neutrophils in tumor immunology.
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Objective To investigate the abnormal expression of Golgi protein 73(GP73) in CD4+ T lymphocytes of the pa-tients with hepatocellular carcinoma (HCC) and its influence of Th1/Th2/Th17 subtype differentiation .Methods Fifty cases of HCC hospitalized in this hospital from May 2015 to February 2016 and 50 healthy volunteers as controls were selected .Peripheral blood was collected and CD4+ T lymphocytes were isolated ;then the expression levels of GP73 and nuclear factor kappa-light-chain-enhancer (NF-κB) in CD4+ T lymphocytes were determined by using RT-qPCR and Western blotting methods ;furthermore ,the se-cretion levels of IL-4 ,IL-17 and IFN-γin the supernatants were examined by using ELISA method .Results GP73 mRNA expres-sion in peripheral blood CD4+ T lymphocytes in the HCC patients were significantly up-regulated compared with the healthy volun-teers ,the difference was statistical difference (P<0 .05) .The expression level of in GP73 overexpression group was significantly in-creased(P<0 .05) ,while which in the GP73 interference group was significantly decreased (P<0 .05) .Over-expression of GP73 in-duced significant increase of IL-4 and IL-17 levels and significant decrease of IFN-γ(P<0 .05);silencing GP73 induced marked de-crease in the expression of IL-4 and IL-17 in CD4+ cells and obvious increase of IFN-γ(P<0 .05) .Conclusion GP73 is over-ex-pressed in peripheral blood CD4+ T cells of HCC patients ,moreover GP73 is very likely to participate in the inflammatory reaction by activating NF-κB to cause the unbalance of Th1/Th2/T17 and promote the occurrence and development of HCC .
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Objective:To observe the expression of IL-12 family subunit genes by real-time quantitative PCR in mice C6 glioma cells,construct the basis of the brain glioma research on IL-12 family in the future.Methods:Mice C6 glioma RNA was abstracted and reversed transcription cDNA.The mice C6 glioma cells mRNA expression influence of IL-12 family subunit genes was compared and analyzed by real-time quantitative PCR.Results: In mice C6 glioma cells, high expression abundances in IL-23a, IL-12a, midlde expression abundances in EBI3, IL-27, low expression abundance in IL-12b.Conclusion: IL-12 families are closely related to the occurrence and development of glioma,IL-12,IL-23 are regarded as the most potential anti-glioma cytokines among them,research de-velopments will bring a new way of brain glioma immune therapy.
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The Toll-like receptors are a kind of pattern recognition receptors,which are expressed in a variety of cells,playing an important role in innate immunity and subsequent acquired immunity.At the same time,they are also involved in the immunity,proliferation,apoptosis and other physiological processes of the cells.Toll-like receptors are also expressed in hematological malignancies and involved in the progress of tumor development,immune escape,resistance,which play a double-edged sword role.In this paper,basic knowledge of TLR molecule and study on hematological tumor were mainly reviewed,aiming to provide a train of thoughts for the treatment of hematologic malignancies.
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As a distinct T cell subset with acknowledged specific function and marker, CD4+CD25+FOXP3+ regulatory T cells are thought to dampen T-cell immunity and to be the main obstacle tempering antitumor immunotherapy. Accumulating evidence has confirmed an increased pool of regulatory T cells both in the peripheral blood and the tumor microenvironment of cancer patients, which are indicative of disease progression, response to therapy, invasive phenotype and prognosis. Therefore, manipulation of regulatory T cells—including depletion, blocking trafficking into tumors, or reducing their differentiation and suppressive mechanisms—and concomitant stimulation of effector T cells, systemically or locally in tumors, represent new strategies for cancer treatment.
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Nutritionally supporting the malnourished tumor bearing host may not benefit the disease outcome, but, rather, may preferentially "feed the cancer". We hypothesized that repletion is beneficial only when it augments an anti-tumor immune response. To support this hypothesis, 240 A/J mice were assigned to isocaloric dietary groups (24%, 5%, or 2.5% protein). On day 14 the mice received either immunogenic C1300- neuroblastoma (NB) or non-immunizing TBJ-NB. On day 21 half of the restricted animals were repleted with 24% protein chow. At day 35, chromium-release cell-mediated cytotoxicity was measured. In the group of mice that received 2.5% protein chow, nutritional repletion specifically augmented anti-tumor activity for C1300-NB which elicits a host immune response (33.78 L.U. (repleted) vs 3.47 L.U. (depleted) p less than 0.01), in contrast, nutritional repletion was detrimental for non-immunizing TBJ-NB, where further depression of cytotoxicity was seen (1.37 L.U. (repleted) vs 2.06 L.U. (depleted) 0 less than 0.01). This suggests that the influence of nutritional repletion in tumor nearing animals is dependent on the integrity of host's anti-tumor immunity.
Subject(s)
Animals , Male , Mice , Body Weight , Immunity, Cellular , Neoplasms, Experimental/immunology , Nutrition Disorders/immunologyABSTRACT
As a potential adjuvant therapy of malignant brain tumors, immunotherapy has aroused the interest of neurooncologists. This review attempt to provide an introduction to the general concepts of tumor immunology and immunological characteristics of brain tumors, especially of gliomas, to promote an understanding of brain tumor immunotherapy(Part II) finally.