Vallet Nicolas, Le Grand Sophie, Bondeelle Louise, Hoareau Bénédicte, Corneau Aurélien, Bouteiller Delphine, Tournier Simon, Derivry Lucille, Bohineust Armelle, Tourret Marie, Gibert Delphine, Mayeur Ethan, Itzykson Raphael, Pacchiardi Kim, Ingram Brian, Cassonnet Stéphane, Lepage Patricia, Peffault de Latour Régis, Socié Gérard, Bergeron Anne, Michonneau David
Université de Paris Cité, INSERM 976, Paris, France.
Pneumology Unit, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Blood. 2022 Dec 8;140(23):2500-2513. doi: 10.1182/blood.2022016926.
Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.
在一项随机3期对照临床试验中，血液系统恶性肿瘤患者接受异基因造血干细胞移植后使用阿奇霉素与复发相关。研究该试验中随机分组患者的240份样本，是一个更好地了解复发潜在机制的独特机会，复发是移植后首要死亡原因。我们对患者样本进行多组学分析，以解读与阿奇霉素摄入及移植后复发恶性肿瘤相关的免疫改变。阿奇霉素与能量代谢途径改变和免疫亚群网络相关，包括偏向免疫调节和耗竭表型的T细胞。在体外，阿奇霉素暴露抑制T细胞对肿瘤细胞的细胞毒性，并通过抑制糖酵解、下调线粒体基因和上调免疫调节基因（尤其是SOCS1）损害T细胞代谢。这些结果表明，阿奇霉素直接影响有利于复发的免疫细胞，这对在恶性肿瘤高危患者中长期使用阿奇霉素治疗提出了警示。ALLOZITHRO试验已在www.clinicaltrials.gov上注册，注册号为#NCT01959100。
