ENOX2 inhibition enhances infiltration of effector memory T-cell and mediates response to chemotherapy in immune-quiescent nasopharyngeal carcinoma,Journal of Advanced Research

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ENOX2 inhibition enhances infiltration of effector memory T-cell and mediates response to chemotherapy in immune-quiescent nasopharyngeal carcinoma
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2023-04-13 , DOI: 10.1016/j.jare.2023.04.001
Ngar-Woon Kam ₁ , Olivier Laczka ₂ , Xiang Li ₂ , John Wilkinson ₂ , Desmond Hung ₃ , Syrus Pak Hei Lai ₃ , Ka Chun Wu ₁ , Sai Wa Tsao ₄ , Wei Dai ₃ , Chi Ming Che ₅ , Victor Ho-Fun Lee ₆ , Dora Lai-Wan Kwong ₆

Affiliation

Introduction

The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive.

Objectives

To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T-cells and response to chemotherapy.

Methods

In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T-cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T-cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment.

Results

NPC predominantly displayed an immune-excluded profile. This “cold-phenotype” was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8⁺ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched.

Conclusion

Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T-cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy.

中文翻译：

ENOX2 抑制增强效应记忆 T 细胞的浸润并介导免疫静止鼻咽癌对化疗的反应

介绍

免疫抑制的肿瘤微环境是化疗的主要障碍。因此，已经设计出不同的化学增敏方法来恢复对一开始免疫静止的癌症的免疫监视。癌症特异性 ENOX2 表达与异常细胞生长相关，并已被提议作为抗癌活性的细胞靶点。然而，ENOX2 对免疫系统和肿瘤细胞之间相互作用的潜在影响仍然难以捉摸。

目标

了解肿瘤内在 ENOX2 介导的T细胞抗肿瘤活性和化疗反应改变的机制。

方法

使用来自鼻咽癌 (NPC) 人体组织的单细胞和批量 RNA 测序数据进行原位多重免疫组织化学来定义肿瘤表型。两种具有不同 ENOX2 表达的 NPC 细胞系被用于共培养平台中，以研究癌细胞/球体与T细胞之间的肿瘤免疫相互作用。在体外和体内测试了顺铂治疗与伊膦酰 (IDX) 抑制 ENOX2 的效果。使用多参数流式细胞术来表征联合治疗的NPC肿瘤人源化小鼠模型中的T细胞浸润。

结果

NPC 主要表现出免疫排斥特征。这种“冷表型”表现出较高的 ENOX2 表达，并与较差的无进展生存期 (PFS) 相关。 IDX 与顺铂的治疗组合可有效促进 CD8 ⁺效应记忆 T 细胞 (Tem) 的分化和动员。该 Tem 特征具有高度细胞毒性，Tem 介导的优先裂解表达较高 ENOX2 的 NPC 细胞。联合治疗的人源化小鼠模型显示肿瘤显着缩小，且肿瘤内富含 Tem。