Mapping immune activity in HPV-negative head and neck squamous cell carcinoma: a spatial multiomics analysis.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Natalie Zwing, Lena Voith von Voithenberg, Laurent Alberti, Sascha Michael Gabriel, Josep M Monné Rodriguez, Romi Feddersen, Jean-Philippe Foy, Francesca Damiola, Nicolas Gadot, Pierre Saintigny, Bruno Gomes
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引用次数: 0

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) exhibits low response rates to immunotherapies, with only about 15-25% of patients responding to monotherapy and 30-45% to combination therapy. This limited effectiveness is attributed to significant intertumor and intratumor heterogeneity, which affects the immunological activity of individual tumors and their regions, thereby influencing immunotherapy outcomes. Various biomarkers at the gene and protein expression levels have been identified to predict the response to immunotherapy in HNSCC.

Methods: In this study, we evaluated intertumor heterogeneity using a 27-gene expression signature to stratify tumors by their immunologic activity status. We investigated intertumor heterogeneity at the molecular and cellular level and further analyzed intratumor spatial heterogeneity within and across these subgroups by using spatial multiomics approaches.

Results: Immunologically active tumors showed increased interferon-γ and interferon-α signaling and upregulation of major histocompatibility complex-I signaling and genes involved in antigen presentation. Chemokines such as CXCL8 and CXCL9, which are crucial for immune cell recruitment, were differentially regulated. The spatial analysis revealed that active tumors tended to show higher autocorrelation of homogeneous regions with immune cell infiltration compared with inactive tumors. Proximity measures showed an increased colocalization of immune cells, particularly CD8+ T cells, T helper cells, and regulatory T cells, near tumor cells in active tumors. Despite this high immune infiltration, HNSCC often has an immunosuppressive microenvironment, which we observed as a colocalization of programmed cell death protein-1+ (PD-1+) cytotoxic T cells and cytotoxic T cells, indicating regional differences in active and exhausted cell ratios. Furthermore, upregulation of JAK-STAT3 signaling in active tumors was potentially associated with immune evasion.

Conclusions: The spatial analysis at multiple omics levels allowed for a detailed investigation of molecular and cell type markers to further distinguish between immunologically active and immunosuppressive microenvironments and their spatial heterogeneity. Our study demonstrates that, besides gene expression signatures, cell colocalization signatures can infer immunological activity in HNSCC, thus predicting immunotherapy response.

绘制hpv阴性头颈部鳞状细胞癌的免疫活性:空间多组学分析。
背景:头颈部鳞状细胞癌(HNSCC)对免疫疗法的应答率较低,只有约15-25%的患者对单一疗法有应答,30-45%的患者对联合疗法有应答。这种有限的有效性归因于肿瘤间和肿瘤内的显著异质性,这会影响单个肿瘤及其区域的免疫活性,从而影响免疫治疗的结果。基因和蛋白表达水平上的各种生物标志物已被确定用于预测HNSCC对免疫治疗的反应。方法:在这项研究中,我们利用27个基因的表达特征来评估肿瘤间的异质性,并根据肿瘤的免疫活性状态对其进行分层。我们在分子和细胞水平上研究了肿瘤间的异质性,并通过空间多组学方法进一步分析了这些亚组内部和之间的肿瘤内空间异质性。结果:具有免疫活性的肿瘤表现为干扰素-γ和干扰素-α信号的增加,主要组织相容性复合体- 1信号和抗原递呈相关基因的上调。趋化因子,如CXCL8和CXCL9,对免疫细胞募集至关重要,受到差异调节。空间分析显示,与非活性肿瘤相比,活性肿瘤与免疫细胞浸润的均质区倾向于表现出更高的自相关性。接近测量显示免疫细胞,特别是CD8+ T细胞、T辅助细胞和调节性T细胞,在活性肿瘤中靠近肿瘤细胞的共定位增加。尽管存在这种高免疫浸润,但HNSCC通常具有免疫抑制微环境,我们观察到这是程序性细胞死亡蛋白-1+ (PD-1+)细胞毒性T细胞和细胞毒性T细胞的共定位,表明活跃细胞和耗尽细胞比例的区域差异。此外,活动性肿瘤中JAK-STAT3信号的上调可能与免疫逃避有关。结论:多组学水平的空间分析允许对分子和细胞类型标记进行详细研究,以进一步区分免疫活性和免疫抑制微环境及其空间异质性。我们的研究表明,除了基因表达特征外,细胞共定位特征还可以推断HNSCC的免疫活性,从而预测免疫治疗反应。
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
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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