Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment

IF 2.2 4区 医学 Q3 HEMATOLOGY
Rebecca Masel , Megan E. Roche , Ubaldo Martinez-Outschoorn
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引用次数: 0

Abstract

The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-β to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8+ T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.

霍奇金淋巴瘤:一种由肿瘤微观和宏观环境形成的疾病
肿瘤微环境(TMicroE)和肿瘤大环境(TMacroE)是典型霍奇金淋巴瘤(cHL)的特征。它们对临床医生来说至关重要,因为它们解释了常见的体征和症状,使我们能够对这些肿瘤进行分类,开发预后和预测性生物标志物,生物成像和新的治疗方法。TMicroE是指癌症细胞对其周围和肿瘤内的影响。癌症细胞在肿瘤远处或外部的作用定义了TMacroE。副肿瘤综合征是由远处癌症或TMacroE影响引起的体征和症状,而不是由癌症细胞直接浸润引起的。最常见的副肿瘤症状是B症状,表现为发烧、发冷、盗汗和/或体重减轻。不太常见的副肿瘤综合征包括影响中枢神经系统、皮肤、肾脏和血液系统自身免疫现象的综合征,包括噬血细胞性淋巴组织细胞增多症(HLH)。白细胞增多、淋巴细胞减少、贫血和低白蛋白血症等副肿瘤体征是预后的生物标志物。cHL中的肿瘤细胞是霍奇金和Reed-Sternberg(HRS)细胞,它们是凋亡前生发中心B细胞,在9p24.1基因座上具有高突变负荷和几乎普遍的遗传改变,主要通过拷贝获得和扩增,并通过PD-L1、JAK-STAT、NFkB和c-MYC强激活信号。在大多数cHL病例中,超过95%的肿瘤细胞是非肿瘤性的。在TMicroE中,HRS细胞通过细胞外小泡、趋化因子、细胞因子和生长因子(如CCL5、CCL17、IL6和TGF-β)大力招募和塑造非肿瘤细胞,以促进前馈炎症循环,从而驱动癌症侵袭性和抗癌免疫逃避。新的单细胞图谱技术提供了关于单核细胞-巨噬细胞、中性粒细胞、辅助T细胞、Tregs、细胞毒性CD8+T细胞、嗜酸性粒细胞、肥大细胞和成纤维细胞在cHL中的作用的关键信息。在此,我们总结EBV对TMicroE和TMacroE的影响。此外,对cHL的TMicroE代谢如何影响生物成像并导致癌症侵袭性进行了综述。最后,我们讨论了TMicroE是如何根据生物成像结果和新型免疫疗法用于风险适应治疗策略的。总之,很明显,如果不了解TMicroE和TMacroE,我们就无法有效管理cHL患者,其临床重要性预计将继续快速增长。
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来源期刊
CiteScore
4.20
自引率
0.00%
发文量
42
审稿时长
35 days
期刊介绍: Best Practice & Research Clinical Haematology publishes review articles integrating the results from the latest original research articles into practical, evidence-based review articles. These articles seek to address the key clinical issues of diagnosis, treatment and patient management. Each issue follows a problem-orientated approach which focuses on the key questions to be addressed, clearly defining what is known and not known, covering the spectrum of clinical and laboratory haematological practice and research. Although most reviews are invited, the Editor welcomes suggestions from potential authors.
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