PO.IM02.06 · 免疫学
长链非编码RNA网络作为三阴性乳腺癌中细胞毒性免疫细胞耗竭的新型主调控因子
Long noncoding RNAs networks as novel master regulators of cytotoxic immune cell exhaustion in triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：乳腺癌是美国女性癌症相关死亡的第二大原因，其中三阴性乳腺癌（TNBC）代表最具侵袭性的亚型。尽管免疫检查点抑制剂（ICI）和CAR-T治疗成为TNBC患者有前景的治疗选择，但其总体有效性有限。这种治疗失败很大程度上受免疫抑制性肿瘤微环境的影响，其中慢性抗原暴露导致细胞毒性淋巴细胞耗竭。耗竭的CD8⁺ T细胞、NK细胞和NKT细胞表现出效应能力减弱和持久性降低，最终损害肿瘤清除。理解维持耗竭的调控机制对于改进免疫治疗至关重要。长链非编码RNA（lncRNAs）已被认可为癌症生物学中转录和表观遗传程序的调控因子；然而，它们对TNBC中免疫细胞耗竭的贡献仍未被探索。
方法：我们分析了来自TNBC肿瘤的单细胞RNA-seq数据集（NCBI/GEO），聚焦于免疫细胞群。我们进行了scRNAseq分析和聚类，以评估特定耗竭标志物（TOX、TIGIT、PDCD1、LAG3）的表达，并进行差异基因表达分析，以鉴定这些耗竭的CD8⁺、NK和NKT细胞亚群中失调的lncRNAs。
结果/未来方向：初步数据鉴定出在TNBC样本的CD8 T细胞、NK和NKT细胞中共有的、与耗竭相关的可变lncRNAs。其中一些候选lncRNAs在某些免疫群体中选择性富集。信号通路分析正在进行中，以评估这些lncRNAs的功能及其在染色质调控、RNA-蛋白支架、转录激活/抑制和代谢应激反应（均为免疫耗竭标志）中的参与。随后，我们将使用RNA干扰和过表达模型在原代人细胞毒性淋巴细胞中对顶级候选lncRNAs进行功能验证，以评估其对耗竭表型和效应功能的影响。
结论：在我们的研究中，我们鉴定出TNBC中一组以前未被认识的lncRNAs，它们可能通过调节TNBC肿瘤生理机能，潜在地驱动跨细胞毒性免疫亚型的免疫耗竭。这些lncRNAs可能对耗竭进展至关重要，通过ASOs或基因沉默逆转其效应可能揭示它们通过维持T细胞持久性在恢复抗肿瘤反应方面的影响。
查看英文原文 English abstract
Background: Breast cancer is the second leading cause of cancer-related deaths among women in the United States, with triple-negative breast cancer (TNBC) representing the most aggressive subtype. Although immune checkpoint inhibitors (ICI) and CAR-T therapy emerge as promising therapy options for TNBC patients, their overall effectiveness is limited. This therapeutic failure is strongly influenced by immunosuppressive tumor microenvironments, where chronic antigen exposure leads to exhaustion in cytotoxic lymphocytes. Exhausted CD8⁺ T cells, NK cells, and NKT cells display diminished effector capacity and reduced persistence, ultimately impairing tumor clearance. Understanding the regulatory mechanisms that sustain exhaustion is critical for improving immunotherapies. Long non-coding RNAs (lncRNAs) have gained recognition as regulators of transcriptional and epigenetic programs in cancer biology; however, their contribution to immune cell exhaustion in TNBC remains unexplored.
Methods: We analyzed single-cell RNA-seq datasets (NCBI/GEO) from TNBC tumors, focusing on immune cell populations. We performed scRNAseq analysis and clustering to assess expression of specific exhaustion markers (TOX, TIGIT, PDCD1, LAG3, as well as differential gene expression to identify dysregulated lncRNAs in those exhausted CD8⁺, NK, and NKT cell subsets.
Results/future directions: Preliminary data identified variable exhaustion-associated lncRNAs shared among CD8 T cells, NK, and NKT cells in TNBC samples. Some of these candidate lncRNAs were selectively enriched in certain immune populations. Signaling pathway analyses are in progress to evaluate the functions of these lncRNAs and their involvement in chromatin regulation, RNA-protein scaffolding, transcriptional activation/repression, and metabolic stress responses, all hallmarks of immune exhaustion. We will then functionally validate top candidate lncRNAs using RNA interference and overexpression models in primary human cytotoxic lymphocytes to assess their impact on exhaustion phenotypes and effector function.
Conclusion: In our study, we identified a previously unrecognized group of lncRNAs in TNBCs, which could potentially drive immune exhaustion across cytotoxic immune subtypes by regulating TNBC tumors physiology. These lncRNAs could be crucial for exhaustion progression, and reversing their effects through ASOs or gene silencing could reveal their influence towards recovering anti-tumor response by maintaining T cell persistence.
利益披露 Disclosure
R. Sanchez, None..
E. E. Chaib Lozano, None..
B. Yang, None..
S. S. Gadad, None..
E. I. Ramos, None.