Abstract
Epithelial ovarian cancer (EOC) is the leading cause of gynaecological cancer-related death in Europe. Although most patients achieve an initial complete response with first-line treatment, recurrence occurs in more than 80% of cases. Thus, there is a clear unmet need for novel second-line treatments. EOC is frequently infiltrated with T lymphocytes, the presence of which has been shown to be associated with improved clinical outcomes. Adoptive T-cell therapy (ACT) using ex vivo-expanded tumour-infiltrating lymphocytes (TILs) has shown remarkable efficacy in other immunogenic tumours, and may represent a promising therapeutic strategy for EOC. In this preclinical study, we investigated the efficacy of using anti-CD3/anti-CD28 magnetic beads and IL-2 to expand TILs from freshly resected ovarian tumours. TILs were expanded for up to 3 weeks, and then subjected to a rapid-expansion protocol (REP) using irradiated feeder cells. Tumours were collected from 45 patients with EOC and TILs were successfully expanded from 89.7% of biopsies. Expanded CD4+ and CD8+ subsets demonstrated features associated with memory phenotypes, and had significantly higher expression of key activation and functional markers than unexpanded TILs. Expanded TILs produced anti-tumour cytokines when co-cultured with autologous tumour cells, inferring tumour cytotoxicity. Our findings demonstrate that it is possible to re-activate and expand tumour-reactive T cells from ovarian tumours. This presents a promising immunotherapy that could be used sequentially or in combination with current therapeutic strategies.
Highlights
Epithelial ovarian cancer has the highest mortality rate of all gynaecological cancers, with more than 4000 deaths each year in the UK [1]
tumour-infiltrating lymphocytes (TILs) can readily be expanded from melanoma biopsies by the addition of high-dose IL-2 alone [36], expanding TILs from other solid tumours has been significantly more challenging
To determine the feasibility of isolating and expanding TILs from epithelial ovarian cancers, we adapted our previous experience with renal cell carcinoma to establish ovarian TIL cultures [23]
Summary
Epithelial ovarian cancer has the highest mortality rate of all gynaecological cancers, with more than 4000 deaths each year in the UK [1]. Infiltration of C D3+ and C D8+ T cells into the tumour has been associated with improved overall and progression-free survival in patients with epithelial ovarian cancer [11, 12]. Ovarian tumours acquire mechanisms to escape immune surveillance, skewing the tumour microenvironment towards a tolerogenic state. These mechanisms include the recruitment of regulatory T cells and MDSCs, expression of co-inhibitory ligands such as PD-L1, reduced antigen presentation and immunosuppressive soluble factors such as TGF-β, IL-10 and IDO [13,14,15,16,17]
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