Characterising the phenotype and function of natural killer cells in patients with prostate cancer

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Hood, S, 2016. Characterising the phenotype and function of natural killer cells in patients with prostate cancer. PhD, Nottingham Trent University.

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Abstract

Background: The detection and diagnosis of prostate cancer was greatly improved with the introduction of the prostate specific antigen (PSA) test and the transrectal ultrasound prostate (TRUS) biopsy. However, PSA levels above the normal range in the blood are not necessarily indicative of prostate cancer and the TRUS biopsy, which provides limited access to the prostate outside of the peripheral zone, only delivers a positive detection rate of ~30%. Although the recently developed transperineal biopsy (TP) method, which is capable of detecting cancer in all regions of the prostate, has improved the positive detection rate to ~60%, this technique is expensive and not widely available. The development of new, non-invasive approaches for detecting the presence of prostate cancer would greatly inform and assist the management of individuals who are suspected of having prostate cancer.
Aim and hypothesis: Evading immune destruction is one of the emerging hallmarks of cancer, as part of which tumours create an immunosuppressive microenvironment which has the potential to modify the phenotype and function of immune cells such as natural killer (NK) cells. The aim of the study is to assess whether alterations in the phenotype and function of NK cells induced by the presence of prostate cancer can be detected in the periphery and be used as parameters for aiding diagnosis and assessing disease progression. The underlying hypothesis of this study was that the presence of prostate cancer would induce detectable changes in the phenotype and function of NK cells in the periphery and that the detection of these would improve the diagnosis and prognosis of prostate cancer.
Methods: Samples were obtained from two cohorts of patients. Patients in the 'TRUS' cohort (n=92) were diagnosed using the TRUS biopsy only, whereas patients in the TP cohort (n=72) were biopsy naïve, had a PSA level of <20ng.ml-1 and underwent simultaneous TRUS (12 cores) and TP biopsies (36 cores). Peripheral blood mononuclear cells (PBMCs) from patients who were defined as having benign disease (Benign, HGPIN, ASAP) or Gleason Grades 6 to 9 disease were analysed for the expression of antigens defining T, B and NK cells (CD3, CD8, CD19, CD56), and NK cell inhibitory (CD85j, NKG2A, LAIR-1) and activation (DNAM-1, NKG2D, NKp30, NKp44, NKp46, 2B4) receptors by flow cytometry.
The influence of prostate cancer on NK cell functional potential was determined by comparing the phenotypes of NK cells that had been 'primed' by co-incubation with CTV-1 human leukaemic cells (a process which was shown to enhance the capacity of NK cells from healthy individuals to kill NK cell 'resistant' PC3 prostate cancer cells) from patients with Gleason grades 6 or 9 disease with those of NK cells from individuals with benign disease and volunteers with no known disease. All of these studies were supported by extensive methodology development.
Results and conclusions: Compared to Gleason 6 patients, a reduced expression of NK cell activating receptors (NKp30, NKp46, 2B4) was observed as the Gleason grade of the patients increased. These patients could not be phenotypically distinguished from patients with benign disease. This suggests that these markers may only have potential for use as biomarkers of progression, not diagnosis. Limited investigations into the ability of NK cells from patients to be primed only found phenotypic differences between healthy volunteers and patients in general (regardless of the presence of disease). Priming of NK cells from patients induced a lower induction of CD137 and CRTAM expression, and a greater down-regulation of NKp46 and CD96 expression compared to that which was observed following the priming of NK cells from healthy volunteers. Although further investigation is needed, no evidence of an immunosuppressive effect by prostate cancer on the phenotype and function of peripheral NK cells was observed in this study.

Item Type:	Thesis
Creators:	Hood, S.
Date:	December 2016
Rights:	This work is the intellectual property of the author. You may copy up to 5% of the work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the owner(s) of the Intellectual Property Rights.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	16 Aug 2017 08:46
Last Modified:	11 Jul 2019 03:00
URI:	https://irep.ntu.ac.uk/id/eprint/31422