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

• Published in: Journal of advanced research 2024-02, Vol.56, p.69-86
• Main Authors: Kam, Ngar-Woon, Laczka, Olivier, Li, Xiang, Wilkinson, John, Hung, Desmond, Lai, Syrus Pak Hei, Wu, Ka Chun, Tsao, Sai Wa, Dai, Wei, Che, Chi Ming, Lee, Victor Ho-Fun, Kwong, Dora Lai-Wan
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Cytotoxicity; ENOX2; Humans; Idronoxil; Memory T Cells; Mice; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Tumor Microenvironment
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2023.04.001

[Display omitted] •High ENOX2 expression is associated with immune excluded/deserted phenotypes in NPC.•ENOX2 inhibitor, idronoxil enhances CD8+ memory T-cell immunity in response to chemotherapy.•Combined treatment with idronoxil and cisplatin enhances tumor response in humanized mice model.•Combined treatment increases CD8+T-cell expansion with cytolytic effector memory (Tem) feature.•T-cell infiltrates and tumor-associated ENOX2 have predictive value for anti-tumor response. 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. To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T-cells and response to chemotherapy. 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. 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. 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 infiltra