Netrin-1阻断抑制肿瘤相关的髓源性免疫抑制细胞、癌症干细胞特性以及减轻对化疗和免疫检查点抑制剂的耐药性。
Netrin-1 blockade inhibits tumor associated Myeloid-derived suppressor cells, cancer stemness and alleviates resistance to chemotherapy and immune checkpoint inhibitor.
发表日期：2023 Aug 26
作者：
Benjamin Ducarouge, Anna-Rita Redavid, Camille Victoor, Ruxanda Chira, Aurélien Fonseca, Maëva Hervieu, Roméo Bergé, Justine Lengrand, Pauline Vieugué, David Neves, Isabelle Goddard, Mathieu Richaud, Pierre-Alexandre Laval, Nicolas Rama, David Goldschneider, Andrea Paradisi, Nicolas Gourdin, Sylvie Chabaud, Isabelle Treilleux, Nicolas Gadot, Isabelle Ray-Coquard, Stéphane Depil, Didier Decaudin, Fariba Némati, Elisabetta Marangoni, Eliane Mery-Lamarche, Catherine Génestie, Séverine Tabone-Eglinger, Mojgan Devouassoux-Shisheboran, Kathryn J Moore, Benjamin Gibert, Patrick Mehlen, Agnes Bernet
来源：
CELL DEATH AND DIFFERENTIATION
摘要：
在化疗或免疫疗法后，药物抗性和癌症复发成为重大的治疗挑战，并且是长期癌症生存的主要限制因素。Netrin-1最初被识别为神经导航信标，但最近已成为癌症治疗的有趣靶点，并正在进行临床研究。我们在这里展示了Netrin-1是乳腺和卵巢癌临床进展的独立预后标志物。癌症干细胞（CSCs）/肿瘤起始细胞（TICs）被认为在临床进展、肿瘤复发和耐药性中起到了作用。我们发现Netrin-1表达与癌症干细胞（CSC）标记物水平之间存在显著相关性。我们还证明，在不同的抗药性小鼠模型中，使用治疗性的Netrin-1阻断抗体干预可以减轻化疗的耐药性，并触发肿瘤复发的有效延迟，这种效果与CSCs的减少相关。我们还证明，Netrin-1干扰限制了肿瘤对免疫检查点抑制剂的耐药性，并提供了将此增强的抗肿瘤疗效与一种被称为多形核粒单核细胞抑制细胞（PMN-MDSCs）的髓源性抑制细胞亚型的招募减少联系的证据。我们已经功能性地证明这些免疫细胞促进了CSCs特征，因此对抗癌治疗产生抗性。综上所述，这些数据支持Netrin-1对癌症干细胞性的直接和间接贡献，并且我们提出了在结合传统化疗和免疫疗法与Netrin-1干扰药物时可能存在的治疗机会的观点。©2023年。作者经ADMCAssociazioneDifferenziamentoeMorteCellulare独家许可。
Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers. Cancer stem cells (CSCs)/Tumor initiating cells (TICs) are hypothesized to be involved in clinical progression, tumor relapse and resistance. We found a significant correlation between netrin-1 expression and cancer stem cell (CSC) markers levels. We also show in different mice models of resistance to chemotherapies that netrin-1 interference using a therapeutic netrin-1 blocking antibody alleviates resistance to chemotherapy and triggers an efficient delay in tumor relapse and this effect is associated with CSCs loss. We also demonstrate that netrin-1 interference limits tumor resistance to immune checkpoint inhibitor and provide evidence linking this enhanced anti-tumor efficacy to a decreased recruitment of a subtype of myeloid-derived suppressor cells (MDSCs) called polymorphonuclear (PMN)-MDSCs. We have functionally demonstrated that these immune cells promote CSCs features and, consequently, resistance to anti-cancer treatments. Together, these data support the view of both a direct and indirect contribution of netrin-1 to cancer stemness and we propose that this may lead to therapeutic opportunities by combining conventional chemotherapies and immunotherapies with netrin-1 interfering drugs.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.