Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Sweden Karolinska Institute, Lund, Sweden.
Department of Pediatrics, Skåne University Hospital, Lund, Sweden.
Oncoimmunology. 2023 Mar 1;12(1):2184130. doi: 10.1080/2162402X.2023.2184130. eCollection 2023.
Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST amplified (MNA) tumors compared to PRE MNA tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA tumor cells were more immunogenic compared to PRE MNA tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA tumor samples. Using an neuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA neuroblastoma by targeting the immune microenvironment.
尽管采取了积极的治疗措施，高危神经母细胞瘤患儿的 5 年无事件生存率仍<50%。虽然大多数高危神经母细胞瘤患者最初对治疗有反应，通常达到完全临床缓解，但许多患者最终仍会出现耐药肿瘤复发。迫切需要新的治疗选择来预防耐药肿瘤的复发。为了了解神经母细胞瘤在治疗下的适应性，我们分析了 22 名神经母细胞瘤患者的 46 个临床肿瘤样本在治疗前（PRE）或治疗后（POST）收集的转录组图谱。RNA 测序显示，与 PRE MNA 肿瘤相比，POST MNA 肿瘤中上调幅度最大（MNA）的许多生物学过程都与免疫相关，与巨噬细胞相关的许多基因显著增加。免疫组化和空间数字蛋白谱证实了巨噬细胞的浸润。此外，与 PRE MNA 肿瘤细胞相比，POST MNA 肿瘤细胞具有更强的免疫原性。为了找到支持治疗后巨噬细胞诱导某些免疫原性肿瘤细胞亚群生长的证据，我们检查了来自 9 名神经母细胞瘤患者的多个临床 PRE 和 POST 肿瘤样本的遗传图谱，结果显示 POST MNA 肿瘤样本中拷贝数异常（CNA）的增加与巨噬细胞浸润呈显著相关。我们使用神经母细胞瘤患者来源的异种移植（PDX）化疗模型进一步表明，用抗 CSF1R 治疗抑制巨噬细胞募集可防止化疗后 MNA 肿瘤的再生长。综上所述，我们的工作支持通过靶向免疫微环境来对抗 MNA 神经母细胞瘤复发的治疗策略。
