乳酸转运蛋白SLC16A1和SLC16A3作为肿瘤免疫生物标志物在胶质瘤中关联肿瘤代谢与免疫逃逸的预后价值

Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma.

作者信息

Zhu Ting, Ge Xiaoqin, Gong Shengping, Guo Shenchao, Tao Qingsong, Guo Jianxin, Ma Ruishuang

机构信息

Department of Radiotherapy and Chemotherapy Ningbo First Hospital Ningbo China.

Central Laboratory of the Medical Research Center Ningbo First Hospital Ningbo China.

出版信息

Cancer Innov. 2022 Oct 12;1(3):229-239. doi: 10.1002/cai2.32. eCollection 2022 Oct.

BACKGROUND

Hypoxic microenvironment is immunosuppressive and protumorigenic, and elevated lactate is an intermediary in the modulation of immune responses. However, as critical lactate transporters, the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.

METHODS

Gene expression in low- and high-grade glioma (LGG and GBM) was evaluated with TCGA database. The TISIDB, TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints.

RESULTS

Compared with normal tissues, a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM, and closely related to the poor prognosis only in LGG. Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflammation in glioma. The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis. TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells, which was correlated to tumor-associated macrophages and neutrophils that are immunosuppressive. SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints (especially PD1, PD-L1, PD-L2, Tim-3) and immunosuppressive factors (TGF-β and IL-10) in glioma. Furthermore, SLC16A3 had a positive correlation to activation markers of tumor-associated neutrophils and chemokines such as CCL2, CCL22, CXCR2, CXCR4 in LGG and CCL7, CCL20 CXCL8 in GBM, which could enhance infiltration of immunosuppressive cells to the tumor microenvironment.

CONCLUSION

In general, our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immunosuppressive cell infiltration, which contributes to immune evasion and a worse prognosis in glioma. Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.

背景

缺氧微环境具有免疫抑制和促肿瘤作用，而乳酸水平升高是免疫反应调节的中间介质。然而，作为关键的乳酸转运体，溶质载体家族16成员1（SLC16A1）和溶质载体家族16成员3（SLC16A3）在胶质瘤免疫浸润和免疫逃逸中的作用尚未完全阐明。

方法

利用癌症基因组图谱（TCGA）数据库评估低级别和高级别胶质瘤（LGG和GBM）中的基因表达。使用肿瘤免疫组库和分析工具（TISIDB）、肿瘤免疫评估资源（TIMER）和CIBERSORT数据库分析SLC16A1或SLC16A3与免疫细胞浸润以及免疫检查点之间的相关性。

结果

与正常组织相比，LGG和GBM中SLC16A1和SLC16A3均显著增加，且仅在LGG中与预后不良密切相关。癌症信号通路富集分析（Cancer SEA）表明，SLC16A1参与胶质瘤缺氧，而SLC16A3促进胶质瘤转移和炎症。基因本体（GO）分析显示，SLC16A3表达与中性粒细胞活化显著相关。肿瘤免疫单细胞图谱（TISCH）显示SLC16A1在胶质瘤细胞上的分布以及SLC16A3在免疫细胞上的分布，这与具有免疫抑制作用的肿瘤相关巨噬细胞和中性粒细胞相关。在胶质瘤中，SLC16A1和SLC16A3被确定与多种免疫检查点（尤其是程序性死亡受体1（PD1）、程序性死亡配体1（PD-L1）、程序性死亡配体2（PD-L2）、T细胞免疫球蛋白黏蛋白3（Tim-3））和免疫抑制因子（转化生长因子-β（TGF-β）和白细胞介素-10（IL-10））紧密相互作用。此外，SLC16A3与LGG中肿瘤相关中性粒细胞的活化标志物以及趋化因子（如CC趋化因子配体2（CCL2）、CC趋化因子配体22（CCL22）、CXC趋化因子受体2（CXCR2）、CXC趋化因子受体4（CXCR4））呈正相关，与GBM中的CC趋化因子配体7（CCL7）、CC趋化因子配体20（CCL20）、CXC趋化因子8（CXCL8）呈正相关，这可增强免疫抑制细胞向肿瘤微环境的浸润。