Garrido-Tapia Macarena, Hernández Carolina J, Ascui Gabriel, Kramm Karina, Morales Marcela, Ga Rate Valentina, Zúñiga Roberto, Bustamante Marco, Aguillón Juan Carlos, Catala N Diego, Ribeiro Carolina H, Molina Mari A Carmen
Laboratorio de Anticuerpos Recombinantes e Inmunoterapia anti tumoral. Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Chile.
Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Chile.
Immunobiology. 2017 Nov;222(11):1043-1051. doi: 10.1016/j.imbio.2017.05.009. Epub 2017 May 23.
NKG2D is an activating receptor expressed on NK cells that binds to a variety of ligands, including MICA and MICB. These cell surface glycoproteins are overexpressed under cellular transformation, thus playing an important role in cell-mediated immune response to tumors. STAT3 is a transcription factor that is constitutively active in cancer. It negatively regulates MICA expression on target cells, while its inhibition enhances NK cell cytotoxicity against tumors. In this work, we aimed to describe the effect of STAT3 signaling inhibition by STA21 on the regulation of MICB expression in gastric adenocarcinoma cells and its effect on the cytotoxic function of NK cells. Treatment of gastric adenocarcinoma cells with STA21 induced an increase in MICB expression and soluble MICB secretion, as well as a variable pattern on effector cell degranulation. Soluble MICB secretion by gastric adenocarcinoma cells was not affected by metalloprotease inhibition. We also observed that primary gastric adenocarcinoma tissue released soluble MICB into the extracellular milieu. Recombinant MICB induced a significant decrease in the levels of NKG2D receptor on effector NK and CD8+ T cells, which correlated with an impaired cytotoxic function. Altogether, our data provide evidence that STAT3 signaling pathway regulates MICB expression on gastric adenocarcinoma cells and that recombinant soluble MICB compromises the cytolytic activity of NK cells.
NKG2D是一种在自然杀伤细胞（NK细胞）上表达的激活受体，它能与多种配体结合，包括MICA和MICB。这些细胞表面糖蛋白在细胞转化过程中过度表达，因此在针对肿瘤的细胞介导免疫反应中发挥重要作用。信号转导和转录激活因子3（STAT3）是一种在癌症中持续激活的转录因子。它负向调节靶细胞上MICA的表达，而对其抑制则增强NK细胞对肿瘤的细胞毒性。在这项研究中，我们旨在描述STA21抑制STAT3信号传导对胃腺癌细胞中MICB表达调控的影响及其对NK细胞细胞毒性功能的作用。用STA21处理胃腺癌细胞可诱导MICB表达增加和可溶性MICB分泌增加，以及效应细胞脱颗粒的可变模式。胃腺癌细胞分泌的可溶性MICB不受金属蛋白酶抑制的影响。我们还观察到原发性胃腺癌组织将可溶性MICB释放到细胞外环境中。重组MICB导致效应性NK细胞和CD8+T细胞上NKG2D受体水平显著降低，这与细胞毒性功能受损相关。总之，我们的数据提供了证据，表明STAT3信号通路调节胃腺癌细胞上的MICB表达，并且重组可溶性MICB损害NK细胞的溶细胞活性。
