Emerging roles of ILC2s in antitumor immunity
Emerging roles of ILC2s in antitumor immunity
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DOI：
10.1038/s41423-022-00918-6
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发表时间：
2022-09
影响因子：
24.1
通讯作者：
Zhao Li;Hanxiao Sun;Z. Gu;J. Qiu
中科院分区：
文献类型：
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作者：
Zhao Li;Hanxiao Sun;Z. Gu;J. Qiu
第二组先天淋巴样细胞(ILC2s)是缺乏T和B细胞抗原受体的ILC亚群[1]。ILC2在转录因子GATA3的表达和标志性细胞因子如IL-5和IL-13的产生方面与CD4+T辅助细胞(Th2)有相似之处[1]。通过表达IL-33、IL-25和胸腺基质淋巴生成素(TSLP)的受体，ILC2对这些警报蛋白迅速做出反应，并在寄生虫感染或过敏的早期阶段成为2型细胞因子的主要来源[1]。越来越多的证据表明，ILC2是肿瘤发生的关键调节因子。然而，ILC2s对肿瘤发展的影响因肿瘤类型、原发或转移肿瘤以及同一肿瘤的不同亚型而不同，具有几个共同的和不同的调节机制。在原发性黑色素瘤中，ILC2s表现出抗肿瘤作用，如在多种小鼠模型中证明，包括BrafCA；PtenloxP；Tyr：：CreERT2小鼠，黑色素瘤细胞的原位模型和黑色素瘤的Ret小鼠模型[2，3]。作为黑色素瘤中最丰富的ILC之一，ILC2的细胞数量随着肿瘤的进展而减少[3]。ILC2s的遗传缺陷，但不是其他ILC，加速了肿瘤的生长，在T/B/ILC缺陷的Rag2-/-IL2RG-/-小鼠中，ILC2祖细胞的恢复足以抑制肿瘤的生长[3]。这一证据有力地表明，ILC2在黑色素瘤中是肿瘤抑制因子。嗜酸性粒细胞是ILC2通过细胞毒活性介导的抗黑色素瘤疗效的中心执行者[3]。ILC2衍生的IL-5和GM-CSF可以促进嗜酸性粒细胞的成熟、存活和激活，并有助于肿瘤的清除[2，3]。肿瘤浸润性ILC2s的功能受多种微环境因素的影响。首先，IL-33促进ILC2产生IL-5和GMCSF。结果，IL-33以ILC2依赖的方式抑制肿瘤生长。值得注意的是，IL-33还触发ILC2表达PD-1，这是一种抑制ILC2活性的免疫检查点分子。一致地，IL-33与α-PD-1抗体的联合治疗先于IL-33单独的抗黑色素瘤作用，支持了这种治疗在未来的有前途的应用[3]。其次，由于Warburg效应，表达黑色素瘤的乳酸脱氢酶产生乳酸，抑制ILC2s产生IL-5，限制其抗肿瘤效果[2]。关于ILC2在原发性黑色素瘤中的作用，有一种争论。虽然IL-33被发现持续抑制肿瘤生长，但α-CD90抗体耗尽ILC2加强了这种作用，这表明ILC2在这方面促进了肿瘤生长[4]。由于α-CD90也系统地消耗ILC3，不同的靶向策略可能会导致在评估ILC2在黑色素瘤中的作用方面存在差异，这要求对未来的靶向策略持谨慎态度。在人类中，已经在黑色素瘤患者中发现了肿瘤浸润性ILC2[3]。此外，对癌症基因组图谱数据库的分析表明，具有高ILC2/Th2信号和IL33的患者的存活率增加，这与小鼠数据显示ILC2具有肿瘤抑制作用一致[3]。虽然ILC2抑制了原发黑色素瘤，但在过敏性炎症的背景下，它们被证明促进黑色素瘤的肺转移，如IL-33或曲霉的鼻腔治疗[5]。从机制上讲，嗜酸性粒细胞的糖酵解通过剥夺葡萄糖和产生乳酸来抑制NK细胞的细胞毒功能。从概念上讲，这些数据似乎与以下发现相矛盾：抑制黑色素瘤肺转移需要嗜酸性粒细胞而不需要呼吸道炎症，而且IL-33-ILC2-嗜酸性粒细胞与…
Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that lack T and B-cell antigen receptors [1]. ILC2s share similarities with CD4+ T helper 2 cells (Th2) in transcription factor GATA3 expression and signature cytokines production, such as IL-5 and IL-13 [1]. By expressing receptors for IL-33, IL-25 and thymic stromal lymphopoietin (TSLP), ILC2s promptly respond to these alarmins and serve as dominant sources for type 2 cytokines at the early phase of parasite infections or allergies [1]. Increasing evidence suggests that ILC2s are critical regulators of tumor development. However, the effects of ILC2s on tumor development differ in terms of tumor types, primary or metastatic tumors, and perhaps different subtypes of the same tumor, with several shared and distinct mechanisms of regulation. In primary melanoma, ILC2s exhibit an antitumor effect, as demonstrated in multiple mouse models, including BrafCA; PtenloxP; Tyr:: CreERT2 mice, orthotopic models of melanoma cells and a Ret mouse model of melanoma [2, 3]. As one of the most abundant ILCs in melanoma, ILC2s decrease in cell number with tumor progression [3]. Genetic deficiency of ILC2s, but not other ILCs, accelerated tumor growth, and the restoration of ILC2 progenitors in T/B/ILC-deficient Rag2-/-Il2rg-/-mice was sufficient to suppress tumor growth [3]. This evidence strongly indicates that ILC2s are tumor suppressors in melanoma. Eosinophils are central executors in ILC2-mediated anti-melanoma efficacy through cytotoxic activities [3]. ILC2-derived IL-5 and GM-CSF can promote eosinophil maturation, survival, and activation and facilitate tumor elimination [2, 3]. The function of tumor-infiltrating ILC2s is affected by several factors in the microenvironment. First, IL-33 enhances IL-5 and GMCSF production by ILC2s. As a result, IL-33 suppresses tumor growth in an ILC2-dependent manner. Notably, IL-33 also triggers ILC2s to express PD-1, an immune checkpoint molecule repressing ILC2 activities. Consistently, combinatorial treatment of IL-33 with α-PD-1 antibody precedes the anti-melanoma effect of IL-33 alone, supporting the promising application of this treatment in the future [3]. Second, lactic acid generated by lactate dehydrogenaseexpressing melanoma, which is attributed to the Warburg effect, inhibits IL-5 production by ILC2s and limits their antitumor efficacy [2]. There is one debate on the role of ILC2s in primary melanoma. While IL-33 was found to suppress tumor growth consistently, depletion of ILC2s by α-CD90 antibody intensified this effect, suggesting that ILC2s promote tumor growth in this context [4]. As α-CD90 also depletes ILC3s systemically, different targeting strategies may cause discrepancies in assessing the role of ILC2s in melanoma, which calls for carefulness for future targeting strategies. In humans, tumor-infiltrating ILC2s have been identified in melanoma patients [3]. Furthermore, analysis of the Cancer Genome Atlas database suggests that patients with high ILC2/Th2 signatures and IL33 have increased survival, in line with mouse data showing that ILC2s are tumor-suppressive [3]. Although ILC2s suppress primary melanoma, they have been shown to promote melanoma lung metastasis in the context of allergic inflammation, as exemplified by intranasal treatment with IL-33 or Aspergillus [5]. Mechanistically, glycolysis of eosinophils, the recruitment of which is driven by ILC2s, suppresses the cytotoxic function of NK cells by glucose deprivation and lactate production. Conceptually, these data seem to contradict the findings that eosinophils are required to suppress melanoma lung metastasis without airway inflammation and that the IL-33-ILC2-eosinophil …