Abstract
BackgroundAdoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. However, clinical responses have so far been limited to patients with hematological malignancies. A potential limiting factor in patients with solid tumors is defective homing of the infused NK cells to the tumor site. Chemokines regulate the migration of leukocytes expressing corresponding chemokine receptors. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer.MethodsBlood and tumor biopsies from 14 primary RCC patients were assessed by flow cytometry and chemokine analysis. Primary NK cells were transduced with human CXCR2 using a retroviral system. CXCR2 receptor functionality was determined by Calcium flux and NK cell migration was evaluated in transwell assays.ResultsWe detected higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients. In addition, CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. However, tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells. Moreover, healthy donor NK cells rapidly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 improved their ability to specifically migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls. The enhanced trafficking resulted in increased killing of target cells. In addition, while their functionality remained unchanged compared with control NK cells, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells.ConclusionsTo increase the success of NK cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells.
Highlights
Adoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment
renal cell carcinoma (RCC) tumors express CXCR2 ligands, while tumor-infiltrating NK cells reduce CXCR2 expression Primary tumor tissues and plasma from 14 RCC patients that underwent nephrectomy were evaluated for the presence of cognate ligands for the chemokine receptor CXCR2 by Bio-Plex chemokine array (Fig. 1a)
The greatest difference in average concentration between tumor and plasma was found for CXCL5 (186-fold gradient) as the chemokine was largely not detectable in patient plasma, while in tumor lysates, its concentration was highest of all analyzed CXCR2 ligands
Summary
Adoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer. Clinical responses in patients with solid tumors treated with adoptively infused NK cells have so far not been beneficial [4, 5]. A potential limiting factor for the success of adoptive NK cell therapy is the inefficient migration of NK cells to the tumor site [6,7,8,9], which may partially explain the poor clinical responses in cancer patients. Improving NK cell infiltration into RCC tumors is an attractive therapeutic option to potentiate the success of NK cell-based therapies and eventually improve clinical responses
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