Dissertation
Dissertation > Medicine, health > Oncology > Respiratory system tumors > Lung tumors

Effect of Anti-tumor Chemotherapy on the Immune Profile and Immune Function of Lung Cancer Patients and Their Significance

Author ZhangLei
Tutor ChuYiWei
School Fudan University
Course Immunology
Keywords Anti-tumor chemotherapy Taxol Non - small cell lung cancer Immune pattern Regulatory T cells CD95 Foxp3 Anti-tumor immune
CLC R734.2
Type Master's thesis
Year 2008
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The tumor is a threat to human health and the life of one of the most important diseases. The anti-tumor chemotherapy drugs and become a common treatment for its killing of tumor cells. However, due to the anti-tumor chemotherapy drugs kill tumor cells while the immune cells also produce damage, so that the reduced number of lymphocytes, in the past that the anti-tumor chemotherapy is not conducive to the subsequent active immunization biological treatment. However, recent research found that the anti-cancer chemotherapy drug role adoptive transfusion of autologous tumor-specific CTL cells get better than the single use Adoptive transfer of anti-tumor effect of lymphocytes. Our group of early animal study also found that: given to anti-cancer chemotherapy drug Taxol injection of tumor-bearing mice after lung cancer antigen peptides DC vaccine Netherlands, has a significant effect of treatment of tumor-bearing mice, the effect is much better than the use of a single tumor vaccine. The results of these experiments is fully prompted the use of anti-cancer chemotherapeutic drugs not only did not suppress the body's immune response, but can induce a beneficial anti-tumor immune response microenvironment. However, no in-depth study at home and abroad for the play to the mechanism of the immunological effects of anti-cancer chemotherapy drug. In view of this, we speculate to Taxol on behalf of the anti-tumor chemotherapy drugs in addition to directly kill tumor cells, but also affect the immune cells and the immune response through the role in the body's immune cells to change the pattern and function of the body's immune, The tumor-bearing body further development of the immune biological therapy that provides benefits. In the present study, we proceed from the existing basic research, begin clinical cases, surgical specimens or peripheral blood lymphocytes of detection of 16 cases of lung cancer patients and 50 cases of lung cancer patients treated with chemotherapy, research Taxol antitumor chemotherapy on the outer periphery of the tumor in patients with immune cell pattern changes, combined with external experimental research Taxol role in the immune cells of the role of mechanisms, further investigate Taxol as a representative of the anti-tumor chemotherapy drugs except cytotoxicity potential role, for anti-cancer chemotherapy joint initiative of the clinical application of biological treatment to provide a theoretical and experimental basis, but also to provide new ideas and new strategies for the treatment of tumors. The development of the first part of the immune pattern of tumor of the lung cancer patient's body and the body of its immune surveillance is always in dynamic change, when the the immune positive effects play a role, can inhibit tumor growth; contrary, when the the immune negative effects dominate, so that the body immune suppression and tumor immune escape and sustained growth. Therefore, non-small cell lung cancer patients for the study, analysis of the patient's immune cell subsets conducive to the understanding of the immune status of the tumor-bearing countermeasures to improve and optimize the anti-tumor immune. Regulatory T cells has been proved to be a disincentive in the anti-tumor immune response with anti-tumor immune effect of the play, and tumor growth is closely related to the change in the proportion of the body. Therefore, we examined 66 patients with non-small cell lung cancer patients and 20 normal control peripheral blood immune cell subsets, in particular, the proportion of regulatory T cell subsets change. The results showed that: Compared with normal controls, peripheral blood leukocytes of cancer patients, lymphocyte absolute number of CD3 T lymphocyte subsets, CD19 B lymphocyte subsets, CD8 < sup> T lymphocyte subsets did not change significantly, but the proportion of lung cancer patients In CD4 T lymphocytes was significantly lower than that in normal controls. On this basis, on the tumor CD4 the CD25 of Foxp3 lymphocyte subsets test results show that the percentage is significantly higher than normal control; CD4 All of CD25 of Foxp3 - T lymphocytes and normal controls did not change significantly. The Tip cancer patients peripheral blood lymphocyte effector T cells did not increase the number of CD4 CD25 T cells mainly CD4 CD25 < / sup> Foxp3 regulatory T cells. The ratio of regulatory T cell subsets of lung cancer patients increased role in tumor development, the tumor regulatory changes in patients with tumor of T lymphocytes in the peripheral blood of patients age, gender, and tumor pathology found that regulatory T lymphocytes in the peripheral blood of cancer patients increased with age, gender, and tumor pathology does not exist, but is closely related with the tumor stage. According to the TNM stage cancer patients the CD4 the CD25 of Foxp3 regulatory T cells in various periods of the cancer are significantly higher than the normal advanced cancer was significantly higher than the cancer early, there is a significant difference. The above results show that: 1) the Treg cell subsets in the peripheral blood of cancer patients body accounted for the proportion of peripheral lymphocytes was significantly higher; 2) With the continuous progress of the tumor course, subsets of Treg cells growing number of Treg cells with tumor The progression is closely related. Tumor immune escape in addition to the low immunogenicity of the tumor cells, the lack of expression of costimulatory molecules makes difficult for the body's immune system to induce an effective immune response, the body's immune negative regulatory effect outside also play an important role. Suggesting that the increase in Treg cell subsets may be one of the important factors induced tumor immune escape. The second part of the anti-tumor immune pattern of change in patients with lung cancer, anti-tumor chemotherapy chemotherapy because of its direct killing effect on tumor cells become one of the most commonly used in the treatment of tumors. The traditional concept that the anti-tumor chemotherapy in killing tumor cells, but also the destruction of the body's normal cells, the body's immune function is severely impaired. Recently, however, studies have found that lymphocytes decreased state, the body's immune pattern changes occurred, is conducive to the generation of immune response. Based on these findings, we envisioned: the proportion of cancer patients lymphocytes can occur redistribution of anti-tumor chemotherapy, the body to rebuild the immune pattern. Therefore, we collected a total of 66 cases of non-small cell lung cancer patients, including 50 patients receiving Taxol-based ranging from 1 to 5 times the anti-tumor chemotherapy for peripheral blood samples of a total of 70 chemotherapy. And these patients during chemotherapy did not receive any treatment of immune-related. By analyzing the proportion of different lymphocyte subsets before and after its anti-tumor cell surface CD molecules change to study the anti-tumor chemotherapy immune pattern. The results showed: leukocytes and lymphocytes in the anti-tumor significantly reduce in lymphocyte subsets CD3 in, T cell subsets was significantly decreased, while CD19 B cells in peripheral lymphoid The percentage of patients in the cells did not change significantly. Focus on changes in T cell subsets, we found that CD4 T cell subsets in anti-tumor chemotherapy after accounting for CD3 T cell ratio was significantly reduced, while the CD8 T cell subsets in the proportion of CD3 T cells did not change significantly. CD4 T cells, we focus on the CD25 changes in the proportion of cell subsets found CD25 of in CD4 The percentage of patients in the cells decreased, while CD25 - increase in the proportion of subsets. Furthermore, we are concerned about the anti-tumor chemotherapy CD25 after T-cell subsets, Teff and Treg cells after chemotherapy, the absolute number of significantly reduced, but Teff T cells share in CD4 , the percentage did not change significantly, while the percentage of Treg cell subsets also significantly reduced. This indicates that the decrease of Treg cells is significantly larger than the the Teff cell subsets, the antitumor chemotherapy Taxol represent selectively reduce Treg cell subsets. The above results show that: 1) anti-tumor chemotherapy Taxol can act on the body's immune cells, the immune cell subsets percentage reallocation; 2) in various T-cell subsets, anti-cancer chemotherapy drugs Thai elements can be selectively lowered the proportion of Treg cell subsets, to some extent weakened due to the increase in Treg cells and induced tumor immune escape. The third part of the anti-tumor chemotherapy selectively lowered the proportion and function of Treg subsets Taxol a family paclitaxel chemotherapy drugs, by inhibiting microtubule formation, directly kill tumor cells play an anti-tumor effect. Our research has Certificate Alpha hormone can not only act on the body's immune cells, and its impact on different cell subsets differ. Thus, we assume that Taxol to play a direct cytotoxic effect, whether there immune mechanisms. Sorting vitro human peripheral blood Treg subsets cells and the control of T effector cell subsets (Teff), in vitro Taxol possible mechanism of action, and experimental validation in clinical cases discussed Taxol the possibility of induction of the immune cell number and function change mechanism. The results showed: Taxol chemotherapy compared Treg cells, a significant increase in apoptosis of Treg cells after chemotherapy, significantly increased the expression of cell surface CD95, but of Teff cell subsets in the role of Taxol, apoptosis ratio not occurred significantly increased cell surface CD95 expression did not change. We also obtained in the clinical cases of experiments similar results. This assumption, Taxol is by enhancing the Treg cell subsets surface expression of CD95, Fas / FasL pathway induced apoptosis of Treg cells, the selective destruction Treg cell subsets. Learn more about Taxol chemotherapy affect the number of Treg subsets at the same time, whether it can affect the function of Treg and Teff cell subsets, vitro proliferation assay to detect the function of Treg and Teff subsets, Treg cells found Taxol chemotherapy immune suppression function significantly down. We also found that compared with no chemotherapy Treg cells, the Treg cell surface Foxp3 mean fluorescence intensity decreased after chemotherapy, Thus, we speculate that Taxol can reduce Foxp3 expression of Treg cells to suppress the negative tone function of Treg cells. The above results show that: 1) Taxol through selective upregulation of Treg cell surface expression of CD95 in apoptosis induced Treg cell subsets; 2) Taxol through the cut of Treg Foxp3 expression strength, weakened Treg cells play immunosuppressive function. Taxol both from the number or function of Treg inhibition produced by downregulating Treg cell subsets in the immunosuppressive effects of anti-tumor immune. The fourth part of the anti-tumor chemotherapy-induced tumor immune microenvironment Treg play an important role in tumor immune escape, and Taxol chemotherapy can selectively act on Treg cell subsets, the lifting of Treg cells toward the Th1 immune pattern has been confirmed in the previous study subsets play in the anti-tumor immune immunosuppressive effect, then the immune and how? study we choose to play an important role in tumor immunity Th1 cell subsets, intracellular flow cytometry. staining method to detect the cancer patients before and after anti-tumor CD4 T cells to secrete the expression of IL-2 and the CD8 T cells secrete IFN-γ expression levels. T cells and the ability of secreting IFN-γ CD8 T cells we found that the anti-tumor chemotherapy, the tumor in patients with peripheral lymphocytes secrete IL-2 capabilities CD4 whether The absolute number or percentage of significantly increased. On the other hand, we also detected signs of activation and memory cell subsets. We detected CD44 activation markers, CD62L mark memory peripheral lymphocytes of cancer patients. Found that CD4 and CD8 T cells with high expression the CD44 high activation markers the CD62L low Memory CD4 and CD8 of T cells in anti-tumor chemotherapy, its share of the outer periphery of the percentage of lymphocytes has increased significantly. The above results show: the role of Treg cells is weakened after the body of a Th1 cell immune response the enhanced; 2) play an anti-tumor effect of the proportion of functional cell populations have also been increased. Therefore, the role of anti-tumor chemotherapy Treg tumor immune escape being discharged, the pattern of immune reconstruction, to provide a basis for the further active immunization and protection. In summary, this study subsets to the the antitumor chemotherapy role of the immune cells of patients with lung cancer as the starting point, to lung cancer patients with surgical resection of the tumor samples and peripheral blood of lung cancer patients treated with chemotherapy for the study, Taxol paclitaxel class of anti-cancer chemotherapy drug research, analysis of lymphocyte numbers and subsets in anti-tumor chemotherapy, found that the proportion of anti-cancer chemotherapy drug role enables the body's immune cells subsets reallocation, and which induced tumor immune escape of one of the important factors of Treg cell subsets reduce the most significant. More important, we found through experiments Taxol through selective upregulation of the Treg surface of CD95 induced Treg apoptosis, while down Treg Foxp3 expression strength weakened Treg suppression function, thereby inhibiting the induction of Treg increased tumor immune escape, adjust the body's immune pattern to provide assurance of the body, for the further use of active immunotherapy. In this study, partially corrected the past that the anti-tumor chemotherapy would seriously damage the body's immunity point in killing tumor cells, as the representative of the potential anti-cancer chemotherapy drug anti-tumor immunity is Thai prime theoretical and experimental basis for the anti- The clinical application of chemotherapy drugs to provide new ideas, and have potential applications in a wide range of social value.

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