PO.CL05.10 · 临床研究
Sphk1-B细胞轴作为癌症中可靶向的免疫调节通路
The Sphk1-B cell axis as a targetable immunoregulatory pathway in cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：鞘氨醇激酶1（SPHK1）/1-磷酸鞘氨醇（S1P）信号轴调控肿瘤进展及肿瘤微环境（TME）内的免疫抑制。虽然已知SPHK1介导的S1P生成可促进卵巢癌生长，但其在塑造B细胞驱动的抗肿瘤免疫中的作用仍不清楚。
方法与结果：在小鼠卵巢癌（ID8 Trp53−/−；Brca2−/−）、黑色素瘤（B16F10）和结直肠癌（MC38）模型中对SPHK1进行基因敲除（SPHK1−/−），导致肿瘤负荷显著降低，同时S1P水平下降约50%。来自SPHK1−/−小鼠的肿瘤显示免疫浸润增加，主要为B淋巴细胞和T淋巴细胞，并富集免疫球蛋白相关和抗原呈递基因特征。流式细胞术和免疫组化证实，肿瘤浸润性CD19+ B细胞、浆细胞增多，激活及抗原呈递标志物（CD69、CD80、CD86、CD40、MHC-II）上调。机制上，SPHK1缺失促进了支持浆细胞分化的代谢重编程，其特征为未折叠蛋白反应升高（XBP1、BiP、GRP94）、氧化磷酸化增加、ATP生成、线粒体生物发生以及FOXO1激活。使用PF543对SPHK1进行药理学抑制,可复现基因敲除的表型，增加浆细胞频率、免疫球蛋白分泌以及激活相关的转录程序。综上所述，我们的数据提示，抑制SPHK1可激活B细胞以增强抗肿瘤免疫应答。
结论：SPHK1/S1P轴抑制使B细胞向强大的代谢适应性、浆细胞分化和抗体介导的抗肿瘤免疫重编程。靶向SPHK1是一种有前景的策略，可增强体液免疫并克服免疫排斥型卵巢癌表型。
意义：本研究揭示了一种此前未被认识的免疫代谢机制，即SPHK1通过该机制控制B细胞功能，凸显了其在增强抗肿瘤免疫和改善免疫治疗反应性方面的治疗潜力。
查看英文原文 English abstract
Background: The sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling axis regulates tumor progression and immune suppression within the tumor microenvironment (TME). While SPHK1-mediated S1P generation is known to promote ovarian cancer growth, its role in shaping B cell-driven anti-tumor immunity remains unclear.
Methods and Results: Genetic ablation of SPHK1 (SPHK1 -/- ) in murine ovarian cancer (ID8 Trp53 -/- ; Brca2 -/- ), melanoma (B16F10), and colorectal cancer (MC38) models resulted in markedly reduced tumor burden accompanied by ~50% reduction in S1P levels. Tumors from SPHK1 -/- mice demonstrated increased immune infiltration, primarily B and T lymphocytes, and enrichment of immunoglobulin-related and antigen presentation gene signatures. Flow cytometry and IHC confirmed enhanced tumor-infiltrating CD19 + B cells, plasma cells, and upregulation of activation and antigen-presentation markers (CD69, CD80, CD86, CD40, MHC-II).Mechanistically, SPHK1 deficiency promoted metabolic reprogramming that supported plasma cell differentiation, characterized by elevated unfolded protein response (XBP1, BiP, GRP94), increased oxidative phosphorylation, ATP generation, mitochondrial biogenesis, and FOXO1 activation. Pharmacologic SPHK1 inhibition using PF543 phenocopied genetic knockout, increasing plasma cell frequency, immunoglobulin secretion, and activation-associated transcriptional programs. Taken together, our data suggest that SPHK1 inhibition activates B cells for enhanced anti- tumor immune response.
Conclusion: SPHK1/S1P axis inhibition reprograms B cells toward robust metabolic fitness, plasma cell differentiation, and antibody-mediated anti-tumor immunity. Targeting SPHK1 represents a promising strategy to boost humoral immunity and overcome immune-excluded ovarian cancer phenotypes.
Impact: This study uncovers a previously unrecognized immunometabolism by which SPHK1 controls B cell function, highlighting its therapeutic potential for enhancing anti-tumor immunity and improving immunotherapy responsiveness.
利益披露 Disclosure
M. Singh, None..
P. Gupta, None..
A. Rahimi, None..
S. Pradeep, None.