Seignez Cédric, Martin Amandine, Rollet Claire-Emmanuelle, Racoeur Cindy, Scagliarini Alessandra, Jeannin Jean-François, Bettaieb Ali, Paul Catherine
EPHE Cancer Immunotherapy Laboratory, EA7269 EPHE-University of burgundy, Dijon, F-21000, France.
Oncotarget. 2014 Nov 30;5(22):11442-51. doi: 10.18632/oncotarget.2556.
Management of advanced colorectal cancer is challenging due to the lack of efficient therapy. The lipid A, OM-174 exhibited antitumor activity in colorectal cancer. We explored the anticancer efficacy of this compound in rats bearing large colorectal tumors in combination with the platinum derivative drugs oxaliplatin and cisplatin. While each drug used alone exhibited partial antitumor activity, sequential treatment with oxaliplatin or cisplatin for one week followed by lipid A injections induced a great regression of colorectal tumors, with more than 95% of rats cured from their tumors. This potent antitumor efficacy of the combined treatments was correlated to the sequential induction of cellular senescence by oxaliplatin, and of apoptosis, mainly triggered by the lipid A. Moreover, a recruitment of tumor-associated neutrophils with N1 phenotype as attested by the expression of inducible nitric oxide synthase was observed with combination of oxaliplatin and lipid A. Neutrophil recruitment within tumor microenvironment was due to oxaliplatin and lipid A-dependent release of neutrophil specific chemoattractants such as cxcl1 and 2. However the N1 phenotype is only dependent of lipid A treatment. These results suggest that the combination of chemotherapy with an immunotherapy is a promising approach to treat patients with advanced colorectal cancer.
由于缺乏有效的治疗方法，晚期结直肠癌的管理具有挑战性。脂多糖A（OM-174）在结直肠癌中表现出抗肿瘤活性。我们探讨了该化合物与铂类衍生物药物奥沙利铂和顺铂联合应用于患有大的结直肠癌肿瘤的大鼠时的抗癌疗效。虽然每种单独使用的药物都表现出部分抗肿瘤活性，但先用奥沙利铂或顺铂连续治疗一周，然后注射脂多糖A，可使结直肠癌肿瘤显著消退，超过95%的大鼠肿瘤得到治愈。联合治疗的这种强大抗肿瘤疗效与奥沙利铂诱导的细胞衰老以及主要由脂多糖A触发的细胞凋亡的顺序诱导相关。此外，观察到奥沙利铂和脂多糖A联合使用时，可诱导肿瘤相关中性粒细胞募集到具有N1表型，这可通过诱导型一氧化氮合酶的表达得到证实。肿瘤微环境中的中性粒细胞募集是由于奥沙利铂和脂多糖A依赖性释放中性粒细胞特异性趋化因子，如cxcl1和2。然而，N1表型仅依赖于脂多糖A治疗。这些结果表明，化疗与免疫疗法联合是治疗晚期结直肠癌患者的一种有前景的方法。
