Understanding immunosuppression in head and neck cancers: validation of prognostic markers and development of NK-cell based immunotherapy
| dc.contributor.author | Upreti, Deepak | |
| dc.contributor.examiningcommittee | Ellison, Cynthia (Pathology) Yao, XiaoJian (Medical Microbiology and Infectious Diseases) Han, Xiaobing (Immunology) Wan, Yonghong (McMaster University) | en_US |
| dc.contributor.supervisor | Kung, Sam (Immunology) | en_US |
| dc.date.accessioned | 2017-03-31T15:21:41Z | |
| dc.date.available | 2017-03-31T15:21:41Z | |
| dc.date.issued | 2017 | en_US |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Head and neck squamous cell carcinoma (HNSCC) arises in the upper aero digestive track that includes cancers of the mouth, throat, larynx and lymph nodes of the neck. It is the sixth most common neoplasm in the world. Despite advances in multi-modality treatments that involve surgery, radiation, and chemotherapy, the 5-year survival rate remained about 50% for the past 35 years. Strategies to improve the survival rate are to identity good prognostic biomarker(s) for early treatment and to design the novel immunotherapies that not only kill the target cells but also prevent cancers from recurrences. We sought to investigate whether CD3ζ in peripheral T cells from patients with HNSCC may serve as a biomarker for the early detection of recurrent or persistent HNSCC in a longitudinal study. Using a cohort of HNSCC patients in a 3-year longitudinal study, our current work showed that change in CD3ζ-chain expression in T cells is an independent predictor of disease status in HNSCC patients and supported the potential use of using flow cytometric measurements of CD3ζ expression of T cells for routine clinical application. Our clinical study suggested that an improved immune phenotype correlated with better disease outcome. Therefore, we are interested in developing immunotherapy that can overcome immunosuppression in HNSCC. Not much is known about the role of natural killer (NK) cells in HNSCC disease progression. NK cells could be therapeutic in inducing anti-tumor immunity. First, NK cells possess effector functions to kill or produce cytokines upon direct target recognition. Second, NK cells can also shape adaptive T-cell immunity through cytokine productions and/or modulation of dendritic cell (DC) functions. We therefore hypothesize that NK cells can induce effective anti-tumor immunity through its direct cytotoxicity and/or modulation of DC functions. Using a clinically relevant mouse model of HNSCC (AT-84), we 5 demonstrated the anti-tumor potential of IL-15 activated NK cells in regressing primary tumors and also in inducting protective immunity upon secondary challenge. Using in vitro and in vivo systems we demonstrated that IL-15 activated NK cells in addition to killing tumor cells also promoted anti-tumor activities via NK-DC crosstalk. Collectively, our data demonstrated that IL- 15 activated NK cells were able to reverse the immunosuppressed DCs to immunostimulatory states which in turn stimulate the T cell and correlated well with tumor regressions. Overall, my thesis work contributed in finding CD3ζ to be a strong and independent predictor of HNSCC disease and IL-15 NK as novel immunotherapy of HNSCC. We hope these findings will ultimately benefit the treatment of HNSCC patients and improve patient’s survival. | en_US |
| dc.description.note | May 2017 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32178 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Spandidos publication, Future medicine, wiley | en_US |
| dc.rights | open access | en_US |
| dc.subject | Neck cancer | en_US |
| dc.subject | Head cancer | en_US |
| dc.title | Understanding immunosuppression in head and neck cancers: validation of prognostic markers and development of NK-cell based immunotherapy | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | yes | en_US |