Wang Yichao, Yuan Hao, Tan Yayun, Wu Li, Zhao Xinchen, Yang Zeyuan, Dai Shaoxing, Yang Naixue
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China.
Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan, China.
Front Oncol. 2025 May 16;15:1592328. doi: 10.3389/fonc.2025.1592328. eCollection 2025.
The tumor microenvironment (TME) plays a crucial role in tumor progression. Recent advancements in single-cell sequencing technology have identified Tc17 cells, a newfound subset of CD8 T cells with a phenotype similar to Th17, within the gastric cancer (GC) microenvironment. However, the role of Tc17 cells are unclear.
We collected 296,879 cells from the single-cell sequencing data of 65 GC samples, along with spatial transcriptomic data from 10 GC samples, to further explore the role of Tc17 cells. Multicolor immunohistochemical staining demonstrated the presence of Tc17 cells in the GC TME. SCENIC analysis was performed to identify the specific transcription factors of Tc17. Pseudotime analysis of T cells was conducted to decipher the differentiation trajectory of Tc17. Additionally, cell-cell interaction analysis revealed the interactions between Tc17 cells and tumor cells. Finally, functional validation through CCK-8 proliferation assays, wound Healing assays, and transwell assays conclusively demonstrated the tumor-promoting effects of IL-17A and IL-26 on gastric tumor cells.
Our results indicate that Tc17 cells are absent from blood and exclusively found in tissues, with greater enrichment in tumor tissues compared to normal tissues. Among CD8 T cells, Tc17 exhibits the weakest cytotoxic capacity and the highest anti-inflammatory profile, suggesting reduced tumor-killing ability. Pseudotime analysis revealed that Tc17 cells ultimately progress towards a state of exhaustion, losing their capacity to eliminate tumor cells. Survival analysis further correlates the presence of Tc17 cells with poor prognosis. Notably, a robust interaction between Tc17 cells and tumor cells was observed in GC. We found that tumor cells can recruit Tc17 cells via the CXCL16-CXCR6 axis, this finding was validated on spatial transcriptome data. And in turn, Tc17 cells may promote tumor progression by secreting IL-17A and IL-26, as functionally corroborated by CCK-8 Assay, wound healing, and transwell assay .
These findings reveal the immunosuppressive role of Tc17 cells in gastric cancer, provide a new perspective for understanding the immunosuppressive mechanism of the gastric cancer tumor microenvironment, and provide a potential target for the development of targeted therapeutic strategies.
肿瘤微环境（TME）在肿瘤进展中起关键作用。单细胞测序技术的最新进展已在胃癌（GC）微环境中鉴定出Tc17细胞，这是一种新发现的CD8 T细胞亚群，其表型与Th17相似。然而，Tc17细胞的作用尚不清楚。
我们从65个GC样本的单细胞测序数据中收集了296,879个细胞，以及10个GC样本的空间转录组数据，以进一步探索Tc17细胞的作用。多色免疫组织化学染色证实了GC TME中存在Tc17细胞。进行SCENIC分析以鉴定Tc17的特异性转录因子。对T细胞进行伪时间分析以解读Tc17的分化轨迹。此外，细胞-细胞相互作用分析揭示了Tc17细胞与肿瘤细胞之间的相互作用。最后，通过CCK-8增殖试验、伤口愈合试验和transwell试验进行功能验证，最终证实了IL-17A和IL-26对胃肿瘤细胞的促肿瘤作用。
我们的结果表明，血液中不存在Tc17细胞，仅在组织中发现，与正常组织相比，肿瘤组织中富集程度更高。在CD8 T细胞中，Tc17表现出最弱的细胞毒性能力和最高的抗炎特征，表示其肿瘤杀伤能力降低。伪时间分析显示，Tc17细胞最终会发展为耗竭状态，失去消除肿瘤细胞的能力。生存分析进一步将Tc17细胞的存在与不良预后相关联。值得注意的是，在GC中观察到Tc17细胞与肿瘤细胞之间存在强烈的相互作用。我们发现肿瘤细胞可以通过CXCL16-CXCR6轴招募Tc17细胞，这一发现已在空间转录组数据上得到验证。反过来，Tc17细胞可能通过分泌IL-17A和IL-26促进肿瘤进展，CCK-8试验、伤口愈合试验和transwell试验在功能上证实了这一点。
这些发现揭示了Tc17细胞在胃癌中的免疫抑制作用，为理解胃癌肿瘤微环境的免疫抑制机制提供了新的视角，并为开发靶向治疗策略提供了潜在靶点。
