Department of Surgery and Immunology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Gene Ther. 2013 Jul;20(7):770-8. doi: 10.1038/gt.2012.96. Epub 2013 Jan 3.
Despite significant strides made in the clinical translation of adoptive immune cell therapies, it is apparent that many tumors incorporate strategies to avoid recognition by receptors expressed on the immune cells, such as NKG2D. Strategies that stabilize the expression of ligands for these receptors may enhance the therapeutic potential of these and related therapies. Doxycycline inhibits matrix metalloproteinases (MMPs) that act to cleave the extracellular domain of MICA/B, ligands for the NKG2D receptor. Doxycycline treatment blocked shedding of MICA/B from a panel of human tumor cells, but also acted to increase their expression and cell surface translocation, possibly through its action on ATM. This meant that many tumor cells displayed increased MICA/B expression and enhanced susceptibility to CIK cells. Interestingly, doxycycline also selectively enhanced the replication of oncolytic vaccinia in many tumor cell lines, leading to increased sensitivity to these therapies. Combination (CIK-oncolytic vaccinia) therapies used in conjunction with doxycycline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and oncolytic viral therapies make it an excellent candidate for rapid clinical testing.
尽管在过继免疫细胞疗法的临床转化方面取得了重大进展，但显然许多肿瘤都采用了策略来避免被免疫细胞上表达的受体识别，例如 NKG2D。稳定这些受体配体表达的策略可能会增强这些治疗方法和相关治疗方法的治疗潜力。强力霉素抑制基质金属蛋白酶（MMPs），这些酶作用于切割 NKG2D 受体的配体 MICA/B 的细胞外结构域。强力霉素治疗阻止了一系列人类肿瘤细胞中 MICA/B 的脱落，但也通过其对 ATM 的作用增加了它们的表达和细胞表面易位，这意味着许多肿瘤细胞显示出增强的 MICA/B 表达和对 CIK 细胞的增强易感性。有趣的是，强力霉素还选择性地增强了许多肿瘤细胞系中溶瘤痘苗病毒的复制，导致对这些疗法的敏感性增加。与强力霉素联合使用的组合（CIK-溶瘤痘苗）疗法导致抗肿瘤作用增强。强力霉素对免疫细胞和溶瘤病毒疗法均具有意想不到的、多效性的有益抗肿瘤作用，使其成为快速临床测试的优秀候选药物。
