Defining tumor-reactive lymphocytes in epithelial ovarian cancer.

Komdeur, F.L. (2014) Defining tumor-reactive lymphocytes in epithelial ovarian cancer. thesis, Medicine.

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Abstract

Epithelial ovarian cancer (EOC) is the most common cause of death from gynecological malignancies. Despite successful initial treatment almost all patients with advanced disease relapse, a prognosis that has not improved in 4 decades. Therefore, new therapeutic strategies are urgently needed. The presence of tumor-infiltrating lymphocytes (TIL) has been associated with a favorable prognosis in several malignancies, including melanoma and ovarian cancer. Adoptive transfer of TIL has shown considerable promise as a new treatment modality in patients with melanoma. The aim of this study was to investigate whether adoptive transfer of TIL could be a potential therapeutic strategy in EOC TIL, isolated from tumor tissue fragments from 22 patients with advanced stage EOC were cultured with high-dose IL-2. TIL phenotype was assessed by flow cytometry and tumor-reactivity was determined with IFN-γ ELISPOT. The tumor-reactive T cell subpopulation was isolated from co-cultures of TIL and tumor cells by selection for CD137, a marker for recent T cell activation. Within this study it was demonstrated that TIL are present within the ovarian cancer tumor tissue. TIL expressed high levels of the immune-inhibitory molecule PD-1 and the immune-stimulatory molecule CD27. It was established that tumor-reactivity of TIL was based on intrinsic tumor specificity. Although augmentation of this tumor reactive specificity has not yet been established, it was demonstrated that the CD137-positive T cells are in fact the tumor-reactive subpopulation of TIL. In order to further investigate adoptive transfer of TIL, a pre-clinical model was developed using the chick chorioallantoic membrane-assay (CAM-assay). Based on the results of this study, adoptive cell transfer therapy with TIL could be an effective new therapeutic strategy in EOC treatment, specifically when combined with approaches that inhibit PD-1 and stimulate CD27 activation. The CAM-assay is considered a valuable and innovative pre-clinical model for in vivo experiments.

Item Type:	Thesis (Thesis)
Supervisor name:	Nijman, Prof. dr. H.W. and Bruyn, Dr. M. de and Wouters, M.C.A.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:00
Last Modified:	25 Jun 2020 11:00
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2074

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