Tharp Marla E, Han Claudia Z, Balak Chris D, Fitzpatrick Conor, O'Connor Carolyn, Preissl Sebastian, Buchanan Justin, Nott Alexi, Escoubet Laure, Mavrommatis Konstantinos, Gupta Mihir, Schwartz Marc S, Sang U Hoi, Jones Pamela S, Levy Michael L, Gonda David D, Ben-Haim Sharona, Ciacci Joseph, Barba David, Khalessi Alexander, Coufal Nicole G, Chen Clark C, Glass Christopher K, Page David C
Whitehead Institute, Cambridge, MA 02142, USA.
These authors contributed equally.
bioRxiv. 2024 Jun 6:2024.06.06.597433. doi: 10.1101/2024.06.06.597433.
Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.
生物性别是癌症的一个重要风险因素，但其潜在的细胞类型和机制仍不清楚。由于肿瘤的发展受免疫系统调控，我们推测性别偏向的免疫相互作用是癌症性别差异的基础。男性偏向的多形性胶质母细胞瘤（GBM）是一种侵袭性强且难治的肿瘤，迫切需要更多创新方法，如考虑性别差异，以改善治疗结果。GBM产生于由小胶质细胞主导的特殊脑免疫环境中，因此我们探究了这种免疫细胞类型中的性别差异。我们分离出成体人类TAM-MG（富含小胶质细胞的肿瘤相关巨噬细胞）和对照小胶质细胞，发现在GBM及低级别肿瘤中存在性别偏向的炎症特征，且与男性的促肿瘤活性和女性的抗肿瘤活性相关。我们证明，由失活X染色体表达或调控的基因促成了这种偏向。总之，我们的结果表明TAM-MG，特别是其性染色体，是GBM中男性偏向的驱动因素。
