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Emerging roles of ILC2s in antitumor immunity

Cellular & Molecular Immunology volume 19, pages 1311–1313 (2022)Cite this article

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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 GM-CSF 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 dehydrogenase-expressing 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].

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Acknowledgements

This work was supported by grants 2020YFA0509103 and 2019YFA0802502 to JQ from the Ministry of Science and Technology of China, grants 32022027 and 31970860 to JQ from the National Natural Science Foundation of China and grants 22ZR1481800 and 20ZR1466900 to JQ from Shanghai Science and Technology Committee (STCSM).

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  1. These authors contributed equally: Zhao Li, Hanxiao Sun.

Authors and Affiliations

  1. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Zhao Li & Ju Qiu

  2. Department of Blood Transfusion, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China

    Hanxiao Sun

  3. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China

    Zhitao Gu

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ZL, HS, ZG and JQ drafted and edited the manuscript. JQ and ZG performed final proofreading of the manuscript.

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Correspondence to Zhitao Gu or Ju Qiu.

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Li, Z., Sun, H., Gu, Z. et al. Emerging roles of ILC2s in antitumor immunity. Cell Mol Immunol 19, 1311–1313 (2022). https://doi.org/10.1038/s41423-022-00918-6

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