ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity
ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity
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DOI：
10.1038/s41586-020-2015-4
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发表时间：
2020-02-19
期刊：
影响因子：
64.8
通讯作者：
Balachandran, Vinod P.
中科院分区：
文献类型：
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作者：
Moral, John Alec;Leung, Joanne;Balachandran, Vinod P.
肿瘤浸润性第2组先天淋巴样细胞引发CD 8（+）T细胞并增强PD-1阻断在胰腺导管腺癌中的抗肿瘤作用。第2组先天淋巴样细胞（ILC 2）调节哺乳动物组织中的炎症和免疫（1，2）。虽然ILC 2在这些组织的癌症中被发现（3），但它们在癌症免疫和免疫治疗中的作用尚不清楚。在这里，我们表明ILC 2浸润胰腺导管腺癌（PDAC）激活组织特异性肿瘤免疫。白细胞介素-33（IL-33）激活原位胰腺肿瘤中的肿瘤ILC 2（TILC 2）和CD 8（+）T细胞，但不激活小鼠异位皮肤肿瘤中的肿瘤ILC 2（TILC 2）和CD 8（+）T细胞，以限制胰腺特异性肿瘤生长。静息和活化的TILC 2表达抑制性检查点受体PD-1。抗体介导的PD-1阻断可缓解ILC 2细胞内在的PD-1抑制，以扩增TILC 2，增强抗肿瘤免疫力，并增强肿瘤控制，将活化的TILC 2鉴定为抗PD-1免疫治疗的靶点。最后，PD-1（+）TILC 2和PD-1（+）T细胞都存在于大多数人PDAC中。我们的研究结果将ILC 2鉴定为用于PDAC免疫疗法的抗癌免疫细胞。更广泛地说，ILC 2作为癌症免疫的组织特异性增强剂出现，可以增强抗PD-1免疫疗法的疗效。由于ILC 2和T细胞共存于人类癌症中并共享刺激和抑制途径，因此共同靶向抗癌ILC 2和T细胞的免疫策略可以广泛适用。
Tumour-infiltrating group 2 innate lymphoid cells prime CD8(+) T cells and amplify the anti-tumour effects of PD-1 blockade in pancreatic ductal adenocarcinoma.Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues(1,2). Although ILC2s are found in cancers of these tissues(3), their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8(+) T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1(+) TILC2s and PD-1(+) T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.