Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA.
Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Cancer Lett. 2024 Nov 1;604:217267. doi: 10.1016/j.canlet.2024.217267. Epub 2024 Sep 20.
Gamma delta T cells (γδT cells) play crucial roles in the immune response against tumors, yet their functional dynamics under different cancer therapies remain poorly understood. Laser Ablative Immunotherapy (LAIT) is a novel cancer treatment modality combining local photothermal therapy (PTT) and intratumoral injection of an immunostimulant, N-dihydrogalactochitosan (glycated chitosan, GC). LAIT has been shown to induce systemic antitumor immune responses in pre-clinical studies and clinical trials, eradicating both treated local tumors and untreated distant metastases. In this study, we used LAIT to treat breast tumors in a mouse model and investigated the effects of LAIT on tumor-infiltrating γδT cells using single-cell RNA sequencing (scRNAseq). We characterized the γδT cells from tumors in control, PTT, GC, and LAIT (PTT + GC) groups, by identifying six distinct subtypes: activated, cytotoxic, cycling cytotoxic, IFN-enriched, antigen-presenting, and IL17-producing γδT cells. Differential gene expression analysis revealed that LAIT significantly upregulated genes associated with T cell activation, leukocyte adhesion, and interferon signaling in treated tumor tissues while downregulating genes involved in protein folding and stress responses. LAIT also uniquely increased the proportion of IL17-producing γδT cells, which correlated with prolonged survival in breast cancer patients, as analyzed using TCGA data. Furthermore, the transcriptomic profiles of γδT cells in LAIT-treated tumors closely resembled those in immune checkpoint inhibitor (ICI)-treated patients, suggesting potential synergistic effects. Our findings indicate that LAIT modulates the γδT cell transcriptome, enhancing their antitumor capabilities and providing a basis for combining LAIT with ICI therapy to improve cancer treatment outcomes.
γδT 细胞（γδT 细胞）在抗肿瘤免疫反应中发挥着至关重要的作用，但它们在不同癌症治疗下的功能动态变化仍知之甚少。激光消融免疫治疗（LAIT）是一种新型的癌症治疗方式，结合了局部光热疗法（PTT）和肿瘤内注射免疫刺激剂 N-二氢半乳糖壳聚糖（糖化壳聚糖，GC）。临床前研究和临床试验表明，LAIT 可诱导全身性抗肿瘤免疫反应，根除治疗局部肿瘤和未治疗的远处转移。在本研究中，我们使用 LAIT 治疗小鼠模型中的乳腺癌，并通过单细胞 RNA 测序（scRNAseq）研究 LAIT 对肿瘤浸润 γδT 细胞的影响。我们通过鉴定六个不同的亚型：激活型、细胞毒性型、循环细胞毒性型、IFN 富集型、抗原呈递型和 IL17 产生型 γδT 细胞，对对照组、PTT、GC 和 LAIT（PTT+GC）组的肿瘤中 γδT 细胞进行了特征描述。差异基因表达分析表明，LAIT 显著上调了与 T 细胞激活、白细胞黏附以及干扰素信号相关的基因，而下调了与蛋白质折叠和应激反应相关的基因。LAIT 还独特地增加了产生 IL17 的 γδT 细胞的比例，这与 TCGA 数据分析中乳腺癌患者的生存延长相关。此外，LAIT 治疗肿瘤中 γδT 细胞的转录组谱与免疫检查点抑制剂（ICI）治疗患者的转录组谱非常相似，表明可能存在协同作用。我们的研究结果表明，LAIT 调节 γδT 细胞的转录组，增强其抗肿瘤能力，并为 LAIT 与 ICI 联合治疗以改善癌症治疗效果提供了依据。
