Xu Feng, Sunderland Alexander, Zhou Yue, Schulick Richard D, Edil Barish H, Zhu Yuwen
Department of Surgery, University of Colorado Anschutz Medical Campus, RC1-North Building, P18-8116, Aurora, CO, 80045, USA.
Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang, 110004, Liaoning, China.
Cancer Immunol Immunother. 2017 Oct;66(10):1367-1375. doi: 10.1007/s00262-017-2031-x. Epub 2017 Jun 16.
Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity. More importantly, TIGIT is upregulated upon NK cell activation via ADCC. Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. Thus, our findings suggest that PVR-like receptors regulate NK cell functions and can be targeted for improving trastuzumab therapy for breast cancer.
曲妥珠单抗是治疗高Her2表达乳腺癌的一线药物。然而，许多癌症对此没有反应，这主要是由于它们对自然杀伤（NK）细胞触发的抗体依赖性细胞毒性（ADCC）具有抗性。已知脊髓灰质炎病毒受体（PVR）样分子对淋巴细胞功能很重要。我们发现所有PVR样受体均在人NK细胞上表达，并且只有TIGIT优先在CD16 + NK细胞亚群上表达。破坏PVR样受体与其在癌细胞上的配体之间的相互作用可调节NK细胞活性。更重要的是，通过ADCC激活NK细胞后，TIGIT会上调。单独或联合阻断TIGIT或CD112R可增强人NK细胞触发的曲妥珠单抗抗肿瘤反应。因此，我们的研究结果表明，PVR样受体调节NK细胞功能，并且可以作为改善曲妥珠单抗治疗乳腺癌的靶点。
