肿瘤微环境中细胞凋亡的多维特征及对黑色素瘤的治疗意义

IF 6.6 2区 医学 Q1 Medicine
Jing Ye, Benliang Wei, Guowei Zhou, Yantao Xu, Yi He, Xiheng Hu, Xiang Chen, Guanxiong Zhang, Hong Liu
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引用次数: 0

摘要

目的 黑色素瘤被广泛用作开发免疫疗法的重要模型,但人们认为可能会出现免疫反应不充分的情况。此外,由于对凋亡在不同肿瘤免疫微环境(TMEs)中的作用了解有限,阻碍了凋亡相关疗法的开发以及与其他治疗策略的结合。方法我们构建了凋亡相关肿瘤微环境特征(ATM),并采用多维分析来了解凋亡在肿瘤微环境中的作用。我们进一步评估了ATM在九个独立队列中的临床应用,并预测了ATM对培养细胞中细胞药物反应的影响。不同的 ATM 组表现出不同的分子特征和生物过程。低ATM组在B细胞活化相关通路中表现出明显的富集。此外,浆细胞的ATM得分最低,凸显了浆细胞在ATM模型中的关键作用。从机理上讲,对浆细胞和其他免疫细胞之间相互作用的分析阐明了它们在协调有效的抗肿瘤免疫反应中的关键作用。值得注意的是,ATM特征与免疫检查点阻断的疗效和各种药物的药物敏感性有关,包括FDA批准和临床使用的靶向血管内皮生长因子信号通路的药物。最后,ATM与三级淋巴结构(TLS)相关,与传统的 "热肿瘤 "相比,ATM具有更强的患者分层能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Multi-dimensional characterization of apoptosis in the tumor microenvironment and therapeutic relevance in melanoma

Multi-dimensional characterization of apoptosis in the tumor microenvironment and therapeutic relevance in melanoma

Purpose

Melanoma is widely utilized as a prominent model for the development of immunotherapy, thought an inadequate immune response can occur. Moreover, the development of apoptosis-related therapies and combinations with other therapeutic strategies is impeded by the limited understanding of apoptosis’s role within diverse tumor immune microenvironments (TMEs).

Methods

Here, we constructed an apoptosis-related tumor microenvironment signature (ATM) and employ multi-dimensional analysis to understand the roles of apoptosis in tumor microenvironment. We further assessed the clinical applications of ATM in nine independent cohorts, and anticipated the impact of ATM on cellular drug response in cultured cells.

Results

Our ATM model exhibits robust performance in survival prediction in multiple melanoma cohorts. Different ATM groups exhibited distinct molecular signatures and biological processes. The low ATM group exhibited significant enrichment in B cell activation-related pathways. What’s more, plasma cells showed the lowest ATM score, highlighting their role as pivotal contributors in the ATM model. Mechanistically, the analysis of the interplay between plasma cells and other immune cells elucidated their crucial role in orchestrating an effective anti-tumor immune response. Significantly, the ATM signature exhibited associations with therapeutic efficacy of immune checkpoint blockade and the drug sensitivity of various agents, including FDA-approved and clinically utilized drugs targeting the VEGF signaling pathway. Finally, ATM was associated with tertiary lymphoid structures (TLS), exhibiting stronger patient stratification ability compared to classical “hot tumors”.

Conclusion

Our findings indicate that ATM is a prognostic factor and is associated with the immune response and drug sensitivity in melanoma.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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