Halvorsen E C, Franks S E, Wadsworth B J, Harbourne B T, Cederberg R A, Steer C A, Martinez-Gonzalez I, Calder J, Lockwood W W, Bennewith K L
Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada.
Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada.
Oncoimmunology. 2018 Oct 16;8(2):e1527497. doi: 10.1080/2162402X.2018.1527497. eCollection 2019.
Regulatory T cells (Tregs) facilitate primary and metastatic tumour growth through the suppression of anti-tumour immunity. Emerging evidence suggests a distinct role for Tregs in mediating tissue repair and barrier integrity in the lungs by IL-33 mediated production of the growth factor amphiregulin (AREG). Dependent on the type of cancer and local microenvironment, AREG may induce tumour cell proliferation, invasion, migration or resistance to apoptosis by signaling through the epidermal growth factor receptor (EGFR). We have found that IL-33 is dramatically increased in and around metastatic tumour foci in the lungs of mice bearing orthotopic murine mammary tumours. We observed that Tregs express significantly more of the IL-33 receptor, ST2, relative to conventional T cells, that ST2 Tregs accumulate in the lungs of metastatic tumour-bearing mice, and that ST2 Tregs produce significantly more AREG than ST2 Tregs. The intranasal administration of recombinant IL-33 increased the proportion of AREG producing ST2 Tregs and enhanced the level of phosphorylated EGFR in the metastatic lungs. While recombinant AREG did not impact mammary tumour cell proliferation despite inducing a dose-dependent increase in phosphorylated EGFR, intranasal administration of AREG resulted in a ten-fold increase in pulmonary metastatic tumour burden . Further, the intranasal administration of recombinant IL-33 significantly increased metastatic tumour burden in the lungs in an amphiregulin-dependent manner. These data identify ST2 Tregs as a microenvironmental source of AREG in the lungs of mice with orthotopic metastatic mammary tumours and highlight an important role for AREG in promoting metastatic tumour growth in the lungs.
调节性T细胞（Tregs）通过抑制抗肿瘤免疫促进原发性和转移性肿瘤生长。新出现的证据表明，Tregs在白细胞介素-33（IL-33）介导的生长因子双调蛋白（AREG）产生过程中，在介导肺组织修复和屏障完整性方面具有独特作用。根据癌症类型和局部微环境的不同，AREG可能通过表皮生长因子受体（EGFR）信号传导诱导肿瘤细胞增殖、侵袭、迁移或抵抗凋亡。我们发现，在原位接种小鼠乳腺肿瘤的小鼠肺部，转移性肿瘤灶及其周围的IL-33显著增加。我们观察到，相对于传统T细胞，Tregs表达显著更多的IL-33受体ST2，ST2 Tregs在携带转移性肿瘤的小鼠肺部积聚，并且ST2 Tregs比ST2 Tregs产生显著更多的AREG。鼻内给予重组IL-33增加了产生AREG的ST2 Tregs的比例，并提高了转移性肺组织中磷酸化EGFR的水平。虽然重组AREG尽管诱导磷酸化EGFR呈剂量依赖性增加，但并未影响乳腺肿瘤细胞增殖，但鼻内给予AREG导致肺转移性肿瘤负荷增加了10倍。此外，鼻内给予重组IL-33以双调蛋白依赖性方式显著增加了肺部转移性肿瘤负荷。这些数据确定ST2 Tregs是原位转移性乳腺肿瘤小鼠肺部AREG的微环境来源，并突出了AREG在促进肺部转移性肿瘤生长中的重要作用。
