Understanding immunosuppression in head and neck cancers: validation of prognostic markers and development of NK-cell based immunotherapy
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Date
2017
Authors
Upreti, Deepak
Journal Title
Journal ISSN
Volume Title
Publisher
Spandidos publication, Future medicine, wiley
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
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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.
Description
Keywords
Neck cancer, Head cancer