Reciprocal interaction of cutaneous T-cell lymphoma cells, the reactive infiltrate, and the lesional microbiome

皮肤 T 细胞淋巴瘤细胞、反应性浸润和病变微生物组的相互作用

• 批准号: 510672168
• 负责人: Professor Dr. Jürgen Christian Becker
• 金额: --
• 依托单位: Institut for Immunologi og Mikrobiologi
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510672168?language=en
• 关键词: Reciprocal; interaction; cutaneous; cell; lymphoma

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is characterized by the proliferation of malignant T cells in a chronic inflammatory environment. Although MF often shows an indolent disease course, a subset of patients exhibits an aggressive course with early tumor development, systemic involvement, and high disease-specific mortality. Currently, it is not known what distinguishes indolent from aggressive MF forms. Given the genetic homogeneity of the disease, extrinsic factors are discussed, e.g., the composition of the cutaneous microbiome. Indeed, we have recently shown that a shift in the cutaneous microbiome is associated with the promotion of epithelial cancers. Notably, bacteria frequently colonize MF lesions and, because of the compromised skin barrier, dysbiosis occurs. Patients with advanced disease frequently die of sepsis rather than of direct organ involvement by the malignancy. On the other hand, clinical observations suggest that bacteria, particularly Staphylococcus aureus (S. aureus), play a direct role in MF progression, e.g. by contributing to a tumor-promoting microenvironment. Our previous studies indicated that bacterial superantigen (SA)-mediated interactions of CTCL cells with the reactive inflammatory infiltrate play a role. Furthermore, we observed that the presence of S. aureus is correlated with the abundance of SA-reactive T-cell receptor (TCR) Vβ families, a finding suggesting that the reactive infiltrate is stimulated by SA, regardless of antigen specificity. The results of preliminary single-cell transcriptomic studies are in line with such tumor-promoting interactions of reactive and malignant T cells. Unfortunately, small patient cohorts – typical in rare diseases – are a challenge for statistical analysis of microbiome data. Thus, the conventional computational methods and models must be accompanied by advanced specialized techniques in order to draw reliable conclusions. Our working hypothesis suggests that there is a reciprocal interaction between the composition and the dynamics of the lesional microbiome and the course of CTCL because of its effect on the tumor microenvironment, particularly the reactive T-cell infiltrate. Thus, we will scrutinize the reciprocal action of malignant cells, the reactive infiltrate, and the microbiome. Specifically, we will determine the correlation of comprehensive single-cell transcriptomic and TCR repertoire analyses of MF lesions composing the malignant CTCL clone, the reactive T-cell infiltrate, and additional stromal cells, with the lesional microbiome. We will validate our observations in a larger series of biobanked formalin-fixed paraffin-embedded clinically annotated, sequential CTCL tissue samples. In selected cases we will use spatially resolved transcriptomics. The expected results will allow discovery of prognostic markers for aggressive disease and developing adequate therapeutic strategies.

真菌病真菌（MF）是皮肤T细胞淋巴瘤（CTCL）最常见的形式，其特征是在慢性炎症环境中恶性T细胞的扩散。尽管MF经常表现出懒惰的疾病病程，但一部分患者表现出侵略性的病程，具有早期肿瘤的发展，全身受累和高疾病特异性死亡率。目前，尚不知道是什么区别于侵略性MF形式。鉴于该疾病的遗传同质性，讨论了外在因素，例如皮肤微生物组的组成。实际上，我们最近表明，皮肤微生物组的转变与上皮癌的促进有关。值得注意的是，细菌经常定居MF病变，并且由于皮肤屏障受损，会发生营养不良。患有晚期疾病的患者经常死于败血症，而不是恶性肿瘤的直接器官受累。另一方面，临床观察结果表明细菌，尤其是金黄色葡萄球菌（金黄色葡萄球菌），在MF进展中起着直接的作用，例如通过促进促进肿瘤的微环境。我们先前的研究表明，细菌超抗原（SA）介导的CTCL细胞与反应性炎性浸润的相互作用起着作用。此外，我们观察到金黄色葡萄球菌的存在与SA反应性T细胞受体（TCR）Vβ家族的抽象相关，这一发现表明，无论抗原特异性如何，SA都会刺激反应性浸润。初步单细胞转录组研究的结果与反应性和恶性T细胞的这种促进性肿瘤相互作用一致。不幸的是，小型患者同类（在罕见疾病中典型的典型）是对微生物组数据统计分析的挑战。这，必须通过高级专业技术来完成常规的计算方法和模型，以得出可靠的结论。我们的工作假设表明，病变微生物组的组成和动力学与CTCL的过程之间存在相互的相互作用，因为它对肿瘤微环境的影响，尤其是反应性T细胞浸润。这是，我们将仔细检查恶性细胞，反应性浸润和微生物组的相互作用。具体而言，我们将确定组成恶性CTCL克隆，反应性T细胞浸润和其他基质细胞的MF病变的全面单细胞转录组和TCR曲目分析的相关性，以及与妇科微生物组的相关性。我们将在一系列较大的生物链菌固定石蜡包裹的临床注释，顺序的CTCL组织样品中验证我们的观察结果。在选定的情况下，我们将使用空间分辨的转录组学。预期的结果将允许发现预后标记以用于侵略性疾病并制定足够的治疗策略。