Tohoku J. Exp. Med., 2012, 226(1)

Identification and Functional Analysis of Ligands for Natural Killer Cell Activating Receptors in Colon Carcinoma

ZHANG ZHANG,¹ TAO SU,¹ LIANG HE,¹ HONGTAO WANG,¹ GANG JI,¹ XIAONAN LIU,¹ YUN ZHANG² and GUANGLONG DONG¹

¹State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, P.R. China
²Department of Immunology, Fourth Military Medical University, Xi'an, P.R. China

Natural killer (NK) cells play important roles in the immune defense against tumor cells. The function of NK cells is determined by a balance between activating and inhibitory signals. DNAX accessory molecule-1 (DNAM-1) and NK group 2 member D (NKG2D) are major NK cell activating receptors, which transduce activating signals after binding their ligands CD155, CD112 and major histocompatibility complex class I-related chains A and B (MICA/B). However, the expression and functions of these ligands in colon carcinoma are still elusive. Here, we show the higher expression of CD155, CD112 and MICA/B in colon carcinoma tissues, although no correlations between the ligands expression and patient clinicopathological parameters were found. The subsequent cytotoxicity assay indicated that NK cells effectively kill colon carcinoma cells. Functional blocking of these ligands and/or receptors with antibodies led to significant inhibition of NK cell cytotoxicity. Importantly, expression of DNAM-1 and NKG2D was reduced in NK cells of colon cancer patients, and this reduction could directly suppress the activation of NK cells. Moreover, colon cancer patients have higher serum concentrations of sCD155 and sMICA/B (soluble ligands, secreted or shed from cells) than those in healthy donors (sCD155, 127.82 ± 44.12 vs. 63.67 ± 22.30 ng/ml; sMICA, 331.51 ± 65.23 vs. 246.74 ± 20.76 pg/ml; and sMICB, 349.42 ± 81.69 vs. 52.61 ± 17.56 pg/ml). The up-regulation of these soluble ligands may down-regulate DNAM-1 and NKG2D on NK cells, ultimately leading to the inhibition of NK cytotoxicity. Colon cancer might be a promising target for NK cell-based adoptive immunotherapy.

keywords —— activating receptors; colon cancer; ligands; natural killer cells; tumor immunotherapy

© 2012 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2012, 226, 59-68

Correspondence: Guanglong Dong, State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shanxi, 710032, P.R. China.

e-mail: guanglong.dong@gmail.com