Zhou Yaxing, Ji Yong, Wang Honggang, Zhang Hai, Zhou Haihua
1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China.
2 Department of Cardiothoracic Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Technol Cancer Res Treat. 2018 Jan 1;17:1533033818780091. doi: 10.1177/1533033818780091.
Colorectal cancer, one of the most commonly diagnosed and lethal cancers worldwide, is accompanied by the disorders of immune system. However, the underlying mechanism is still not fully understood. In this study, our goal was to determine whether interleukin 33 promotes tumorigenesis and progression of colorectal cancer through increased recruitment of tumor-infiltrating ST2 regulatory T cells in CT26 tumor-bearing mice. We found that the mRNA or protein levels of interleukin 33, soluble ST2, and membrane ST2 were elevated in the serum of tumor-bearing mice when compared to WT mice. The mRNA levels of interleukin 33, soluble ST2, and membrane ST2 were also elevated in the tissue of tumor-bearing mice when compared to surrounding nontumor muscular tissues. In addition, the frequency of ST2L regulatory T cells was significantly increased in both tumor tissue and spleen of tumor-bearing mice. Higher protein levels of interleukin-4, -10, and -13 were also observed in the serum or the tumor homogenates of tumor-bearing mice. We found exogenously administered recombinant mouse interleukin 33 promoted tumor size and induced tumor-infiltrating ST2L regulatory T cells in tumor-bearing mice while neutralizing interleukin-33 or ST2L inhibited tumor size and decreased ST2L regulatory T cells. Furthermore, ST2L regulatory T cells from tumor tissue were also able to suppress CD4CD25T cell proliferation and interferon γ production. Altogether, our findings demonstrate the critical roles of interleukin 33 in promoting colorectal cancer development through inducing tumor-infiltrating ST2L regulatory T cells, and inhibition of interleukin-33/ST2L signaling maybe a potential target for the prevention of colorectal cancer.
结直肠癌是全球最常见且致命的癌症之一，常伴有免疫系统紊乱。然而，其潜在机制仍未完全明确。在本研究中，我们的目标是确定白细胞介素33是否通过增加CT26荷瘤小鼠肿瘤浸润性ST2调节性T细胞的募集来促进结直肠癌的发生和进展。我们发现，与野生型小鼠相比，荷瘤小鼠血清中白细胞介素33、可溶性ST2和膜ST2的mRNA或蛋白水平升高。与周围非肿瘤肌肉组织相比，荷瘤小鼠组织中白细胞介素33、可溶性ST2和膜ST2的mRNA水平也升高。此外，荷瘤小鼠肿瘤组织和脾脏中ST2L调节性T细胞的频率显著增加。在荷瘤小鼠的血清或肿瘤匀浆中也观察到白细胞介素-4、-10和-13的蛋白水平更高。我们发现，外源性给予重组小鼠白细胞介素33可促进荷瘤小鼠肿瘤大小增加并诱导肿瘤浸润性ST2L调节性T细胞，而中和白细胞介素-33或ST2L可抑制肿瘤大小并减少ST2L调节性T细胞。此外，肿瘤组织中的ST2L调节性T细胞也能够抑制CD4CD25T细胞增殖和干扰素γ的产生。总之，我们的研究结果表明白细胞介素33通过诱导肿瘤浸润性ST2L调节性T细胞在促进结直肠癌发展中起关键作用，抑制白细胞介素-33/ST2L信号通路可能是预防结直肠癌的潜在靶点。
