肿瘤细胞治疗研究
英文原题：NKR(+)CD8(+) T cells and iNKT cells protect mice from AOM/DSS-induced colorectal cancer under conditions of IFNγ-mediated hyperinflammation.
NKR(+)CD8(+) T cells and iNKT cells protect mice from AOM/DSS-induced colorectal cancer under conditions of IFNγ-mediated hyperinflammation.
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在 IFNγ水平升高的 Yeti 小鼠中，NKR + CD8 + T 细胞以依赖 iNKT 细胞的方式抑制 CRC 发展，提示在 IFNγ过度炎症期间，NKR + CD8 + T 细胞与 iNKT 细胞协同驱动针对 CRC 的最佳抗肿瘤免疫应答。我们的发现突出了一种通过增强 IFNγ依赖性抗肿瘤应答来治疗 CRC 的潜在免疫治疗策略。
干扰素-γ（IFNγ）是免疫监视和炎症中的关键细胞因子，然而由于其同时参与肿瘤抑制和免疫逃逸，其在结直肠癌（CRC）中的确切作用仍存在争议。尽管NK 细胞受体（NKR）+ CD8 + T细胞和恒定自然杀伤T（iNKT）细胞有助于抗肿瘤免疫，但这些细胞在IFNγ介导的炎症条件下如何调控CRC进展仍不清楚。
在具有IFNγ介导的过度炎症的杂合Yeti小鼠中建立了氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）诱导的CRC模型。使用流式细胞术和组织学，我们评估了肿瘤负荷、组织病理学以及肿瘤组织中的免疫细胞浸润。IL15处理诱导了NKR + CD8 + T细胞，其抗肿瘤疗效通过过继转移得到验证。使用iNKT细胞缺陷的Yeti/Jα18敲除（KO）小鼠评估了iNKT细胞的功能贡献。通过使用基因集富集（GSE）和蛋白互作网络（STRING）分析分析来自非转移性和转移性CRC患者的公共转录组数据集，确定了临床相关性。
我们发现，与野生型（WT）对照相比，Yeti小鼠的CRC发展显著减缓。此外，这些IFNγ介导的抗肿瘤免疫应答归因于表达NKRs的CD8+ T细胞对肿瘤浸润的增加。过继转移实验证明，NKR⁺CD8⁺ T细胞是强效的抗肿瘤效应细胞。Yeti小鼠中肿瘤浸润性iNKT细胞表现出IFNγ产生增强和IL10产生减少。缺乏iNKT细胞的Yeti小鼠表现出NKR+ CD8+ T细胞对肿瘤浸润的减少，表明iNKT细胞，尤其是产生IFNγ的那些，对于控制CRC发展至关重要。通过GSE和STRING分析，我们发现与转移性患者相比，非转移性患者表现出增强的IFNγ应答，这反映为IFNγ相关基因本体论类别的富集程度更高。
Interferon-gamma (IFNγ) is a pivotal cytokine in immune surveillance and inflammation, yet its precise role in colorectal cancer (CRC) remains controversial due to its dual involvement in tumor suppression and immune evasion. Although natural killer cell receptor (NKR) + CD8 + T cells and invariant natural killer T (iNKT) cells contribute to anti-tumor immunity, how these cells regulate CRC progression under IFNγ-mediated, inflammatory conditions remains unclear.
An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC model was established in heterozygous Yeti mice with IFNγ-mediated hyperinflammation. Using flow cytometry and histology, we evaluated tumor burden, histopathology, and immune cell infiltration in tumor tissues. NKR + CD8 + T cells were induced by IL15 treatment, and their anti-tumor efficacy was validated by adoptive transfer. The functional contribution of iNKT cells was assessed using iNKT cell-deficient Yeti/Jα18 knockout (KO) mice. Clinical relevance was determined by analyzing public transcriptomic datasets from non-metastatic and metastatic CRC patients using gene set enrichment (GSE) and protein interaction network (STRING) analyses.
We found that Yeti mice display significantly blunted CRC development compared to wild-type (WT) controls. Furthermore, these IFNγ-mediated anti-tumor immune responses were attributed to increased tumor infiltration by CD8 + T cells expressing NKRs. Adoptive transfer experiments demonstrated that NKR⁺CD8⁺ T cells are potent anti-tumor effectors. Tumor-infiltrating iNKT cells in Yeti mice exhibited enhanced IFNγ and reduced IL10 production. Yeti mice lacking iNKT cells exhibited reduced tumor infiltration by NKR + CD8 + T cells, indicating that iNKT cells, particularly those producing IFNγ, are critical for controlling CRC development. Through GSE and STRING analyses, we found that non-metastatic patients exhibited increased IFNγ responses, reflected by greater enrichment of IFNγ-related gene ontology categories, compared with metastatic patients.
NKR + CD8 + T cells in Yeti mice with elevated IFNγ levels suppress CRC development in an iNKT cell-dependent manner, suggesting that NKR + CD8 + T cells and iNKT cells cooperate to drive optimal anti-tumor immune responses against CRC during IFNγ hyperinflammation. Our findings highlight a potential immunotherapeutic strategy for CRC by reinforcing IFNγ-dependent anti-tumor responses.
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