Laboratory of Human CarcinogenesisCenter for Cancer ResearchNational Cancer InstituteBethesdaMD.
Department of General SurgeryTianjin Medical University General HospitalTianjinChina.
Hepatology. 2021 Mar;73(3):1045-1060. doi: 10.1002/hep.31412.
Hepatocellular carcinoma (HCC) is an aggressive malignancy which is often associated with a complex tumor microenvironment attributable to etiology-induced cellular inflammation. γδ T cells are known to detect and react to chronic inflammation, which is linked to cancer development, progression, and metastasis. Our recent genomic study revealed an increased infiltration of several immune cell types, including γδ T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis.
Here, we quantified the amount of γδ T cells using a γδ T-cell-specific gene signature in 247 Chinese HCC patients. We also validated the γδ T-cell signature in American HCC patients. Additionally, such an association was only found in tumor transcriptomic data, but not in adjacent nontumor transcriptomic data, suggesting a selective enrichment of γδ T cells in the tumor microenvironment. Moreover, the γδ T-cell signature was positively correlated with the expression of natural killer cell receptor genes, such as NKG2D and cytolytic T-cell genes granzymes and perforin, suggesting a stronger T-cell-mediated cytotoxic activity. Furthermore, we found that the γδ T-cell-specific gene expression is positively correlated with the expression of chemokine (C-C motif) ligand 4 (CCL4)/chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor type 1 (CCR1)/C-C chemokine receptor type 5 (CCR5), the receptors for γδ T cells. We validated these results using immunohistochemical analysis of formalin-fixed, paraffin-embedded tumor biopsies from 182 HCC patients. Moreover, we found evidence of CCL4/CCL5-mediated recruitment of γδ T cells both in vitro and in a murine orthotopic Hepa1-6 HCC model.
We propose that CCL4/CCL5 may interact with their receptor, CCR1/CCR5, which may facilitate the recruitment of γδ T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of γδ T cells in tumors may enhance antitumor immunity and improve patients' prognosis.
肝细胞癌（HCC）是一种侵袭性恶性肿瘤，通常与病因引起的细胞炎症相关的复杂肿瘤微环境有关。γδ T 细胞已知可检测和反应慢性炎症，而慢性炎症与癌症的发生、发展和转移有关。我们最近的基因组研究表明，在与预后良好相关的泰国 HCC 亚型的肿瘤微环境中，几种免疫细胞类型（包括 γδ T 细胞）的浸润增加。
在这里，我们使用 γδ T 细胞特异性基因特征在 247 例中国 HCC 患者中定量了 γδ T 细胞的数量。我们还验证了该 γδ T 细胞特征在美国 HCC 患者中的存在。此外，这种关联仅在肿瘤转录组数据中发现，而在相邻的非肿瘤转录组数据中未发现，提示 γδ T 细胞在肿瘤微环境中选择性富集。此外，γδ T 细胞特征与自然杀伤细胞受体基因（如 NKG2D）和细胞毒性 T 细胞基因颗粒酶和穿孔素的表达呈正相关，表明 T 细胞介导的细胞毒性活性更强。此外，我们发现 γδ T 细胞特异性基因表达与趋化因子（C-C 基序）配体 4（CCL4）/趋化因子（C-C 基序）配体 5（CCL5）和 C-C 趋化因子受体 1（CCR1）/C-C 趋化因子受体 5（CCR5）的表达呈正相关，这些是 γδ T 细胞的受体。我们使用 182 例 HCC 患者的福尔马林固定、石蜡包埋肿瘤活检的免疫组织化学分析验证了这些结果。此外，我们在体外和小鼠原位 Hepa1-6 HCC 模型中发现了 CCL4/CCL5 介导的 γδ T 细胞募集的证据。
我们提出 CCL4/CCL5 可能与其受体 CCR1/CCR5 相互作用，这可能有助于从外周血或肿瘤周围区域招募 γδ T 细胞到肿瘤区域。因此，肿瘤中 γδ T 细胞的浸润增加可能会增强抗肿瘤免疫并改善患者的预后。
