Development of a T cell based cancer immunotherapy by using the induced pluripotent stem cell

Cancer is one of the leading health issues that has caused tremendous impacts to both affected individuals and the whole society. Conquering cancer is imminent; however, with the currently available therapeutic approaches, it is somewhat difficult to achieve a cure in the clinics. Finding novel and more potent treatments to cancer is urgent.;For example, in the clinical trials by using the adoptive T cell transfer (ACT)-based cancer immunotherapy, giving cancer patients either tumor-infiltrating or geneticallyengineered T cells have showed significant improvements in the context of tumorregression and patient-survivals. These studies have suggested a new strategy to treat cancer patients in addition to the currently available ones. However, a major problem of this strategy is the shortage of the T cells for the treatment. In some patients, there are no tumor-infiltrating T cells; in others, their peripheral blood-derived T cells are either anergic or senescent, hence are not suitable for subsequent processing. Exploring new sources of T cells is critical to design a more effective cancer immunotherapy by using the ACT-based approach.;Embryonic stem cells (ESCs) and their derivatives are considered premium candidates for regenerative medicine because of their self-renewable nature and capability of targeted differentiation. In previous work, it was shown that different types of stem cells such as embryonic and hematopoietic stem cells (HSCs) could be induced to develop into both lymphoid and myeloid tissues, under different lineage driving forces. Fitting in this scenario, T cells could also be generated from stem cells by different approaches. Hence, using stem tissue becomes a potential mechanism for getting adequate numbers of cells for T cell-based cancer immunotherapy. Moreover, there is another advantage of using T cells that are directly derived from stem cells; the induced T cells are naive-phenotyped because they have no access to potential antigens. Based on current models of T cell development, naive T cells are more persistent than effector T cells. In addition, naive T cells have the capability to develop into memory stem T cells and central memory T cells, which are substantially longer-lived than any other subtypes of T cells. In summary, stem cells could potentially serve as new sources of large numbers of T cells; however, technical difficulties and ethical concerns have both limited the broad application of stem cells, especially ESCs.;The recent staging of induced pluripotent stem (iPS) cell technology might help change the uncertain fate of using stem cells in both basic research and clinical study. By overexpressing a certain combination of different genetic factors into terminally differentiated somatic cells, it is found that those cells are able to reprogram back into the stem-like cells which highly resemble ESCs in many aspects. This approach could theoretically reprogram any type of somatic cell back into stem cells. This discovery could technically and ethically break the barrier of using embryonic tissues and other types of somatic stem cells. In the field of regenerative medicine, many reports have shown that iPS cells have become alternative choices to replace ESCs in tissue engineering, which further indicates that iPS cells might be the substitutes of ESCs in generating T cells for cancer immunotherapy.;Following an in-depth understanding of the human immune system, a new concept of cancer immunology has been outlined. It is found that the immune system has its own mechanism to eliminate dysfunction or deregulated self-tissue. However, in many cancer patients, their anti-cancer immune systems were compromised due to different explanations. Supplementing some of the defective immune system components in cancer patients has been shown a promising result in which tumor regression has been observed.;My doctoral thesis research is part of the big picture trying to understand the possible utilization of iPS cells in cancer immunotherapy. This broad scheme contains many different directions and my work mainly focuses on the T cell, especially the cytotoxic T lymphocytes (CTLs). The hypothesis of my research is that the iPS cell is identical to ESC in the context of T lineage differentiation, and furthermore, the iPS cell can be engineered and induced into antigen-specific T cells to enhance immune surveillance against cancer. (Abstract shortened by UMI.).