Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
J Immunother Cancer. 2022 Apr;10(4). doi: 10.1136/jitc-2021-004151.
Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice.
, local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. , locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics.
Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.
回顾性临床试验报告称，在癌症手术中注射局部麻醉剂后，局部复发率降低，总生存率提高。在这里，我们研究了在临床实践中使用的六种局部麻醉剂的抗癌作用。
局部麻醉剂诱导癌细胞应激的迹象，包括氧化磷酸化抑制，自噬诱导以及内质网（ER）应激，其特征是 X 盒结合蛋白 1（XBP1s）mRNA 的剪接，激活转录因子 6（ATF6）的切割，真核翻译起始因子 2α激酶 3（EIF2AK3，俗称 PERK）磷酸化和随后的激活转录因子 4（ATF4）上调。eIF2α 磷酸化和自噬都需要与 ER 应激相关的真核翻译起始因子 2α激酶 3（EIF2AK3，也称为 PERK）。局部麻醉剂还激活了免疫原性细胞死亡的两个标志，即 ATP 和高迁移率族蛋白 1 蛋白（HMGB1）的释放，但未能导致钙网蛋白（CALR）从内质网向质膜易位。局部注射麻醉剂可降低几种在免疫功能正常的小鼠中建立的肿瘤模型中的肿瘤生长并提高生存率。PD-1 阻断的系统免疫疗法或重组 CALR 蛋白的肿瘤内注射增加了局部麻醉剂的抗肿瘤作用。局部麻醉剂未能在免疫缺陷小鼠中或在无法激活 ER 应激或自噬的癌症中诱导抗肿瘤作用，这分别是由于 EIF2AK3/PERK 或 ATG5 的敲除。解偶联剂可抑制氧化磷酸化并诱导自噬和 ER 应激，模拟了局部麻醉剂的免疫依赖性抗肿瘤作用。
总而言之，这些结果表明局部麻醉剂在癌细胞中诱导了一种具有治疗相关性的免疫原性应激反应模式。
