The IFNγ-CIITA-MHC II axis modulates melanoma cell susceptibility to NK-cell-mediated cytotoxicity.

IF 4.5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Lena C M Krause, Rixa-Mareike Köhn, Christian Ickes, Julia Lenger, Jonas Fischer, Sabrina Cappello, Ivan Bogeski
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Abstract

Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer-(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL- and NK-cell-mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK-cells in anti-melanoma immunity, we performed 2D and 3D co-culture-based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK-cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK-cell-mediated killing (NKmK). We found that cytokines such as IFNγ play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFNγ, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK-cell-based immunotherapies and offers novel insights into melanoma immune escape mechanisms.

IFNγ-CIITA-MHC II轴调节黑色素瘤细胞对nk细胞介导的细胞毒性的易感性。
黑色素瘤是最致命的一种皮肤癌,由于其遗传异质性和高转移潜力,对治疗构成了重大挑战。近年来,基于细胞毒性T细胞(CTL)的免疫疗法取得了显著进展,自然杀伤细胞(NK)的治疗潜力也越来越被认识到。然而,对CTL和nk细胞介导的免疫疗法的耐药机制阻碍了有效的治疗。为了评估nk细胞在抗黑色素瘤免疫中的独特作用,我们在不同条件下进行了基于2D和3D共培养的细胞毒性试验。我们的研究结果揭示了长时间暴露于原代nk细胞后黑色素瘤细胞的保护性表型。通过将实验数据与生物信息学分析相结合,我们确定了黑色素瘤细胞适应nk细胞介导的杀伤(NKmK)的关键基因和途径。我们发现细胞因子如IFNγ在抑制NKmK中起主要作用,其中MHC II表面表达是一个关键因素。靶向控制MHC II表达并受IFNγ影响的主调节因子CIITA,可显著降低黑色素瘤细胞对NKmK的耐药性。这项研究提供了克服nk细胞免疫疗法耐药性的潜在策略,并为黑色素瘤免疫逃逸机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Oncology
Molecular Oncology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
11.80
自引率
1.50%
发文量
203
审稿时长
10 weeks
期刊介绍: Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.
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