Lung cancer is the leading cause of mortality and morbidity in the world. In Taiwan, lung cancer is the second cause of cancer death in men and the first in women. Although the five-year survival rate in the early stage, operable non-small cell lung cancer patients was ranged from 60% in stage IA patients to 15% in stage IIIA patients, over 85% of patients were of advanced and inoperable stage at diagnosis. Their medium survival was around six to nine months. New generations of chemotherapy or newly developed target therapy can significantly prolong the medium survival in statistics but the range is only one to three months, which is of limited significance in clinical practice, suggesting a limitation of current modalities of treatment. Chinese herbal medicines have a long history and show effectiveness in benefiting the maintenance of health and the recovery from diseases. Among them, Astragalus-based Chinese herbs have shown to increase effectiveness of platinum-based chemotherapy when combined with chemotherapy in advanced stage non-small cell lung cancer. Despite the fact that many Chinese herbal medicines have shown a pro-apoptotic effect on tumor cells in vitro, none of them have been demonstrated a tumorocidal effect in clinical practice, when used alone. Moreover, Astragalus has revealed an anti-apoptotic effect on cells, suggesting a non-tumorocidal function of Astragalus formula in benefiting cancer therapy.~Studies have shown that external or internal stimuli can induce cell transformation. As a result, dys-regulation in cell growth, DNA repair, cell proliferation and apotosis may occur. Normal committed tissue cells can transform into undifferentiated, multi-potential malignant cells. Normally, the competent immune system can recognize the transformed abnormal cells, undergo immune editing, activate cytotoxic cells to eradicate the abnormal cells and, finally, prevent malignant cell transformation. But through unknown mechanisms, the malignant cells may escape from immune surveillance, release chemokines, growth factors and other mediators to drive the change of inflammatory cells. Consequently, the anti-tumor function of immune cells is suppressed, leading to an environment in favor of development and metastasis of malignant cells. From the experiment of animal model and some observations on malignancy, researchers have suggested that malignant cells can release mediators, which can activate pre-myeloid suppressors and promote myeloid-derived suppressor cells development. The myeloid-derived suppressor cells can further trigger cytotoxic T cell apoptosis, and may shift the macrophages toward M2 subtype, inhibit the Th1 cell, and initiate other immune suppressive mechanism. The functions of NK cells and regulatory T cells are altered, resulting in a disturbance of anti-tumor immune function. All these can further create an environment with a benefit for malignant cell growth and advancement. Astragalus-based formula may confer its surval advantage in cancer patients through modulating the immune system and reversing the immunosuppressive microenvironment.~The lung cancer study in the Department of Thoracic Medicine has demonstrated that the myeloid-derived suppressor cells, cytotoxic T cells, Treg cells and monocytes play a critically important role in mediating immune alterations in patients with advanced stage, non-small cell lung cancer. In this three-year proposal, we aim to study the role of one Astragalus-based formula : Qingshu Yiqi Tang in reversing the immune alterations in patients with advanced stage, non-small cell lung cancer who receive 1st line doublet chemotherapy of cisplatin plus doxetaxel（or Pemetrexed for adenocarcinoma）and 2nd line target therapy of erlotinib. We will target on the modulating effect of Qingshu-Yiqi-Tang on the expression and function of myeloid-derived suppressor cells, Th1, Th2, cytotoxic T cells, NK cells, and the subtypes of monocytes (M1-like vs M2-like). Flow cytometry will be used to study the cell subtypes. The related cytokines and growth factors in serum or supernatant of culture, including IL4, IL-6, IL13, VEGF, TGFb, GM-CSF, will be analyzed using ELISA and FACS microbeads array. The expression of iNOS and arginase I will be verified using WB, IP and RT-PCR. The molecular mechanism related to the cell function will be studied using ex vivo cell co-culture model. All the patients will be followed up for three years at maximum. We hope that, via this three-year proposal, we can explore the possible mechanism of the Astragalus-based formula : Qingshu-Yiqi-Tang(清暑益氣湯) in modulating and reversing immunosuppression in advanced stage, non-small cell lung cancer patients. Through this study, we would found a basis for further comprehensive research on the mechanism of other Chinese herbal medicines for benefiting lung cancer therapy.
The myeloid-derived suppressor cells (MDSCs) can further trigger cytotoxic T cell apoptosis, and may shift the macrophages toward M2 subtype, inhibit the Th1 cell, and initiate other immune suppressive mechanism. The functions of NK cells and regulatory T cells are altered, resulting in a disturbance of anti-tumor immune function. All these can further create an environment with a benefit for malignant cell growth and advancement. Astragalus-based formula may confer its survival advantage in cancer patients through modulating the immune system and reversing the immunosuppressive microenvironment.~The investigators aim to study the role of Qingshu-Yiqi-Tang in reversing the immune alterations in patients with advanced stage, non-small cell lung cancer who receive 1st line doublet chemotherapy of cisplatin plus doxetaxel（or Pemetrexed for adenocarcinoma）and 2nd line target therapy of erlotinib. The investigators can explore the possible mechanism of the Astragalus-based formula: Qingshu-Yiqi-Tang in modulating and reversing immunosuppression in advanced stage, non-small cell lung cancer patients.