Induction of NKG2D Ligands and Increased Sensitivity of Tumor Cells to NK Cell-mediated Cytotoxicity by Hematoporphyrin-based Photodynamic Therapy

Abstract

Natural killer (NK) cells are important innate effector cells which can irradicate tumor cells through specific interactions between activating receptors on NK cells and their cognate ligands on cancer cells. Recently, it has been known that induction of activating NKG2D ligands including MHC class I chain-related (MIC) and UL16-binding protein (ULBP) families on tumor cells by various stresses makes them more susceptible to NK cell-mediated cytotoxicity. Therefore, it was investigated whether sublethal dose of hematoporphyrin-based photodynamic therapy (PDT) could up-regulate NKG2D ligands on tumor cells and increase the susceptibility of cancer cells against NK cells. Treatment with sublethal dose of hematoporphyrin-based PDT increased mRNA transcription and surface expression of ULBP1 and ULBP2 genes in SNU-1 human gastric tumor cell line and MICA/B, ULBP1, ULBP2 and ULBP3 genes in SW-900 human lung cancer cell line. These results were followed by increased susceptibility of cancer cells to NK cell-mediated cytotoxicity after sublethal PDT, which was abolished by addition of a blocking NKG2D mAb. Therefore, it could be suggested that the effect of hematoporphyrin-based PDT might be mediated in part by the increased susceptibility to NK cells via induction of NKG2D ligands on tumor cells, which survived after treatment with PDT.

Keywords:

• Photodynamic therapy
• Hematoporphyrin
• NKG2D ligands
• NK cells

ACKNOWLEDGEMENTS

This study was supported by the Mid-career Researcher Program through an NRF grant funded by the MEST (No. 2009-0084444), MRC program MOST/KOSEF (R13-2005-009), the National R&D Program for Cancer Control, Ministry for Health, Welfare & Family Affairs, Republic of Korea (0920050), and the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (No. A091047).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.