IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8+ T-cell responses
IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8+ T-cell responses
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DOI：
10.1080/2162402x.2020.1758606
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发表时间：
2020-01-01
期刊：
影响因子：
7.2
通讯作者：
Leclerc, Claude
中科院分区：
文献类型：
--
作者：
Dadaglio, Gilles;Fayolle, Catherine;Leclerc, Claude
抗肿瘤免疫由Th 1 CD 4（+）和CD 8（+）T淋巴细胞介导，其诱导肿瘤特异性细胞溶解，而Th 17 CD 4（+）T细胞被描述为促进肿瘤生长。在这里，我们探讨了IL-17对治疗性疫苗诱导小鼠肿瘤排斥反应的能力的影响，这些疫苗使用了几种已知能引发Th 1或Th 17型免疫的佐剂。用Th 1佐剂疫苗免疫小鼠诱导高水平的产生IFN-γ的T细胞，而用Th 17促进佐剂注射则触发了产生IL-17和IFN-γ的T细胞的刺激。然而，尽管它们能够诱导强烈的Th 1应答，但这些促进Th 17的佐剂未能诱导肿瘤的根除。此外，IL-17 A的全身施用强烈降低了Th 1佐剂化疫苗在两种不同肿瘤模型中的治疗效果。这种抑制作用与全身递送的IL-17 A抑制CD 8（+）T细胞应答诱导的能力相关。在中性粒细胞耗竭的小鼠中，IL-17 A对诱导CD 8（+）T细胞应答的抑制作用被消除，清楚地证明了这些细胞在IL-17 A诱导抗肿瘤应答的抑制作用中所起的作用。这些结果表明，即使强烈的Th 1型反应有利于肿瘤控制，同时激活的Th 17细胞可能会重新定向或削减肿瘤特异性免疫通过涉及中性粒细胞的机制。这项研究证实，IL-17在有效的抗肿瘤T细胞应答的发展中起着有害的作用，因此可能通过抑制CTL应答强烈影响免疫治疗的效率。
Antitumor immunity is mediated by Th1 CD4(+) and CD8(+) T lymphocytes, which induce tumor-specific cytolysis, whereas Th17 CD4(+) T cells have been described to promote tumor growth. Here, we explored the influence of IL-17 on the ability of therapeutic vaccines to induce the rejection of tumors in mice using several adjuvants known to elicit either Th1 or Th17-type immunity. Immunization of mice with Th1-adjuvanted vaccine induced high levels of IFN-gamma-producing T cells, whereas injection with Th17-promoting adjuvants triggered the stimulation of both IL-17 and IFN-gamma-producing T cells. However, despite their capacity to induce strong Th1 responses, these Th17-promoting adjuvants failed to induce the eradication of tumors. In addition, the systemic administration of IL-17A strongly decreases the therapeutic effect of Th1-adjuvanted vaccines in two different tumor models. This suppressive effect correlated with the capacity of systemically delivered IL-17A to inhibit the induction of CD8(+) T-cell responses. The suppressive effect of IL-17A on the induction of CD8(+) T-cell responses was abolished in mice depleted of neutrophils, clearly demonstrating the role played by these cells in the inhibitory effect of IL-17A in the induction of antitumor responses. These results demonstrate that even though strong Th1-type responses favor tumor control, the simultaneous activation of Th17 cells may redirect or curtail tumor-specific immunity through a mechanism involving neutrophils. This study establishes that IL-17 plays a detrimental role in the development of an effective antitumor T cell response and thus could strongly affect the efficiency of immunotherapy through the inhibition of CTL responses.