Groza Diana, Gehrig Sebastian, Kudela Pavol, Holcmann Martin, Pirker Christine, Dinhof Carina, Schueffl Hemma H, Sramko Marek, Hoebart Julia, Alioglu Fatih, Grusch Michael, Ogris Manfred, Lubitz Werner, Keppler Bernhard K, Pashkunova-Martic Irena, Kowol Christian R, Sibilia Maria, Berger Walter, Heffeter Petra
Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria.
Oncoimmunology. 2018 Feb 16;7(5):e1424676. doi: 10.1080/2162402X.2018.1424676. eCollection 2018.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistance - often due to insufficient drug delivery - is still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gram-negative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.
结直肠癌（CRC）是最常被诊断出的癌症之一，也是全球癌症死亡的主要原因。在疾病晚期，CRC常表现出腹膜腔中的（多个）转移病灶，全身化疗无法有效靶向这些病灶。这是导致预后不良的一个主要因素。奥沙利铂是晚期CRC最常用的全身治疗选择之一。然而，耐药性——通常是由于药物递送不足——仍然阻碍着治疗的成功。奥沙利铂的抗癌活性除了包括DNA损伤外，还具有很强的免疫原性成分。因此，本研究的目的是研究细菌幽灵（BGs）作为佐剂免疫刺激剂对奥沙利铂疗效的影响。BGs是具有独特免疫刺激潜力的革兰氏阴性细菌的空包膜。事实上，我们能够证明BGs与奥沙利铂治疗的联合对CT26同种异体移植具有强大的协同抗癌活性，在这种CRC癌病小鼠模型中延长了生存期，甚至实现了完全缓解。这种协同效应基于免疫原性细胞死亡的增强诱导和有效T细胞反应的激活，从而导致长期的抗肿瘤记忆效应。综上所述，BGs的联合应用增强了奥沙利铂抗癌反应的免疫原性成分，因此代表了晚期CRC化疗中一种有前景的天然免疫佐剂。
