Tumor Immunology and Immunotherapy
Michael I. Nishimura, PhD
Phong Le, PhD
Herb Mathews, PhD
Jose Guervara, PhD
Jose Guevara-Patino, MD, PhD
• CD8+ T-cells
Our long-term objective as academic scientists is to develop curative T cell-based approaches against cancer. To achieve this goal, the scientific effort of our lab is focused on understanding how memory CD8+ T cells can be generated, maintained, and rescued in tumor-bearing individuals.The protective immune response against tumors and invading intracellular pathogens relies on the vigorous attack of cytotoxic T lymphocytes (CTLs). Based on these responses, T cell immunotherapy has emerged as one of the most promising approaches for the treatment of malignancies. However, important hurdles have emerged, foremost of which are the physiological state of tolerance or ignorance of the immune system towards self-antigens, tumor-induced suppression (i.e. TGF-β) and T cell exhaustion. Hence, the objective of our lab is to provide a mechanistic basis for how signal cues on T cells can be exploited to overcome these hurdles. We are focusing on the role of the activating NK receptor, NKG2D, on CD8+ T cells in the prevention of T cell suppression by tumor-produced TGF-β and functional exhaustion. Thus, by maintaining their cytolytic function and persistence in tumor-bearing hosts, we will augment anti-tumor CD8 T cell responses. In CD8+ T cells, engagement of the NK receptor, NKG2D, results in augmented T cell receptor (TCR) activation and function, which facilitates recognition and destruction of stressed target cells. Beyond this canonical function, our lab is interested in how NKG2D signaling in CD8+ T cells drives fundamental molecular changes that impact CD8+ T cell function and effector/memory programs. Our goal is to characterize NKG2D signaling biochemically and functionally in relationship with tumor-induced suppression and exhaustion. Altogether, these studies bring important biological and practical information necessary for the design of future immunologically based clinical trials against melanoma and other forms of cancer.
Phong Thanh Le, PhD
• T-cell development
My laboratory studies the biology of human thymic epithelial cells (TECs) in the developmental process of T cells from hematopoietic stem cells (HSCs). We interrogate human T cell development in vitro by establishing TEC lines from the pediatric human thymus. These TEC lines are then genetically modified to identify critical genes that support T cell development from the CD34pos HSCs. We have generated human TEC lines that overexpress the Notch ligand Delta-like 4, the physiological ligand for the Notch receptor; Notch signaling is essential for initiating T lineage commitment in HSCs and promotes their development into mature T cells. Other molecules being studied are WNT3A and two critical components of the thymoproteasome, PSMB8, and PSMB11; both are involved in the generation of thymic- specific peptides for the generation of mature CD4 and CD8 T cells through the positive selection process. Lastly, a cell-free system established with exosomes from TEC lines is being investigated as an off-the-shelf “drug” to promote HSCs to develop into T cells. Our work has a significant impact on developing T cells with antitumor activity for cell-based immunotherapy and ameliorating T cell engraftment in patients receiving HSC transplant as a treatment for hematopoietic malignancies.
|Michael Nishimura, PhD
Professor, Surgery and Cancer Biology
Associate Director, Cancer Center Translations Research
Program Director, Immunologic Therapeutics
• Tumor immunology
My laboratory has had a long-standing interest in the genetics of T cell receptor (TCR) genes that mediate recognition of tumor and viral antigens. In addition to understanding the relationship between the genetics of the TCR and the function of T cells, we have developed the approach of engineering T cells from any patient to express TCR genes isolated for tumor reactive T cell clones. The resulting TCR gene-modified T cells can recognize tumors in vitro and in vivo. Therefore, it is now possible to provide any patient with a source of their own T cells capable of targeting their malignancies.
Despite our ability to custom generate tumor reactive T cells for patients, early clinical trials suggest TCR gene modified T cells are not as effective at tumor infiltrating T cells in treating cancer patients. To improve the therapeutic efficacy of TCR gene modified T cells, my laboratory has several ongoing projects designed to understand the biology of TCR transduced T cells. Using a combination of mouse in vivo tumor models, in vitro human studies, and clinical trials, my laboratory is studying the mechanisms to increase the persistence and function of adoptively transferred T cells. We also have mouse and human studies designed to overcome tumor-induced immune suppression. Another critical problem my laboratory is addressing is how to circumvent tumor immune escape. And finally, we are developing novel approaches for generating TCR transduced T cells to treat cancer.