SLC1A1调控谷氨酰胺代谢异常介导NK/T细胞淋巴瘤坏死性凋亡的机制研究

Natural killer/T-cell lymphoma (NKTCL) is the malignant proliferation of CD56+/cytoCD3+ lymphocytes, which is prevalent in Asian population, characterized by highly aggressiveness and inferior survival prognosis. The pathogenic mechanism and therapeutic targets of NKTCL remain unwarranted. In our previous study, serum metabolomic profile was assessed and revealed aberrant “alanine, aspartate, and glutamate metabolism” in NKTCL, as compared to healthy volunteers. Besides, RNA-sequencing of fresh tumor biopsies found recurrent SLC1A1-RIC1 gene fusion, whose partner gene SLC1A1 was overexpressed in approximately 80% of NKTCL patients and mediated transmembrane transportation of extracellular amino acid metabolite glutamine (Gln) into tumor cells. Tumor expression of SLC1A1 correlated with serum level of Gln, serving as prognostic factors in patients treating with asparaginase (ASP)-containing anti-metabolism therapy. Based on preliminary studies, we proposed following hypothesis: SLC1A1 mediates cellular dependence of Gln and accelerates cell proliferation and malignant transformation; ASP hydrolyzes Gln in tumor microenvironment and subsequently induces necroptotic cell death. To further investigate therapeutic efficacy and molecular mechanism of ASP targeting SLC1A1-mediated dysregulated cancer metabolism, future studies will focus on the biological function and molecular mechanism of SLC1A1-mediated Gln-dependence, as well as increased ASP-sensitivity through targeting the metabolic vulnerability and inducing necroptotic cell death, providing rationale for targeted anti-metabolism therapy in NKTCL.

NK/T细胞淋巴瘤（NKTCL）高发于亚洲人群，呈高侵袭性、预后差、致病机制不明，是亟待攻克的医学难题。我们前期血清代谢组学检测发现NKTCL存在丙氨酸、门冬氨酸和谷氨酸代谢通路异常；肿瘤组织RNA测序发现重现融合基因SLC1A1-RIC1，其伙伴基因SLC1A1在约80%的患者中高表达，介导谷氨酰胺（Gln）跨膜转运。肿瘤组织SLC1A1表达水平与血清Gln水平相关，是患者预后不良的分子标志。基于前期工作基础提出以下假说：SLC1A1诱导Gln依赖促进淋巴瘤细胞增殖和恶性转化，门冬酰胺酶（ASP）通过水解肿瘤微环境中Gln，诱导肿瘤细胞坏死性凋亡。为进一步探讨ASP靶向SLC1A1介导代谢异常的治疗作用及其分子机制，我们将在细胞和动物模型中研究SLC1A1生物学功能及其诱导Gln依赖，ASP靶向代谢易损点诱导肿瘤细胞坏死性凋亡的具体作用机制，为NKTCL抗代谢靶向治疗奠定扎实的理论基础。

代谢重编程在淋巴瘤发生发展中发挥重要作用。基于门冬酰胺酶的抗代谢治疗被广泛应用于谷氨酰胺代谢异常的NK/T细胞淋巴瘤（NKTCL）中。.申请人应用液相色谱-质谱技术对36例NKTCL患者的血清样本进行检测以明确NKTCL血清代谢谱特征。通过整合代谢组数据和肿瘤组织的RNA测序数据，明确门冬酰胺酶的潜在治疗靶点EAAT3（SLC1A1基因编码）。在NK-92和SNK-6细胞株和斑马鱼移植瘤模型中深入研究SLC1A1的生物学功能、代谢流特征、淋巴细胞增殖活力及药物敏感性。.NKTCL患者的血清代谢谱表现为异常谷氨酰胺代谢。其中，SLC1A1是谷氨酰胺代谢的重要调控因子。体内外研究均证实，SLC1A1过表达可促进肿瘤细胞对谷氨酰胺的转运，激活谷胱甘肽代谢流，诱导肿瘤细胞谷氨酰胺依赖性，导致肿瘤细胞增殖及恶性转化。值得一提的是，肿瘤细胞SLC1A1高表达与PD-L1下调显著相关。SLC1A1过表达细胞与外周血单个核细胞共培养，可显著抑制CD3+/CD8+T细胞活力。门冬酰胺酶可靶向SLC1A1介导的谷氨酰胺依赖，从而杀伤肿瘤细胞。此外，培门冬酶还可恢复SLC1A1过表达肿瘤细胞导致的T细胞免疫损伤。在接受基于门冬酰胺酶的抗代谢治疗的临床队列中，免疫组化EAAT3阳性组患者的无进展生存和总生存均显著优于阴性组患者，是独立的预后良好因素。.SLC1A1是一个谷氨酰胺转运蛋白，通过重编程谷氨酰胺代谢，介导肿瘤细胞增殖，促进其对门冬酰胺酶治疗的敏感性。此外，SLC1A1还可调控肿瘤细胞表面PD-L1表达，这一发现为协同靶向代谢易损点和免疫抑制状态肿瘤微环境的临床应用提供了重要理论依据。