An IL6-Adenosine Positive Feedback Loop between CD73+ γδTregs and CAFs Promotes Tumor Progression in Human Breast Cancer
An IL6-Adenosine Positive Feedback Loop between CD73+ γδTregs and CAFs Promotes Tumor Progression in Human Breast Cancer
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CD73( ) γ δ Tregs 和 CAF 之间的 IL6-腺苷正反馈环促进人类乳腺癌的肿瘤进展
DOI：
10.1158/2326-6066.cir-19-0923
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发表时间：
2020-10-01
影响因子：
10.1
通讯作者：
Huang, Jian
中科院分区：
文献类型：
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作者：
Hu, Guoming;Cheng, Pu;Huang, Jian
肿瘤微环境通过募集和扩增抑制性免疫细胞如调节性T细胞（Treg）来诱导免疫抑制，以促进癌症进展。在这项研究中，我们证明了肿瘤浸润性CD 73（+）γ δ T细胞是人类乳腺癌中的主要T细胞，并且比CD 4（+）或CD 8（+）T细胞发挥更有效的免疫抑制活性。我们进一步证明，癌症相关成纤维细胞（CAF）来源的IL 6，而不是TGF β 1，通过IL 6/STAT 3途径诱导配对正常乳腺组织的CD 73（+）gdTreg分化，产生更多的腺苷，成为有效的免疫抑制性T细胞。CD 73（+）γ δ T细胞通过腺苷/A2 BR/p38 MAPK信号通路促进CAFs分泌IL 6，形成IL 6-腺苷正反馈环。CD 73（+）γ δ Treg浸润也损害了CD 8（+）T细胞的杀瘤功能，与患者预后不良显著相关。这些数据表明，CD 73（+）γ δ T细胞和CAF之间的IL 6-腺苷环对促进人类乳腺癌的免疫抑制和肿瘤进展很重要，这可能是肿瘤免疫治疗的关键。
The tumor microenvironment induces immunosuppression via recruiting and expanding suppressive immune cells such as regulatory T cells (Treg) to promote cancer progression. In this study, we documented that tumor-infiltrating CD73(+) gamma delta Tregs were the predominant Tregs in human breast cancer and exerted more potent immunosuppressive activity than CD4(+) or CD8(+) Tregs. We further demonstrated that cancer-associated fibroblast (CAF)-derived IL6, rather than TGF beta 1, induced CD73(+) gdTreg differentiation from paired normal breast tissues via the IL6/STAT3 pathway to produce more adenosine and become potent immunosuppressive T cells. CD73(+) gamma delta Tregs could in turn promote IL6 secretion by CAFs through adenosine/A2BR/p38MAPK signaling, thereby forming an IL6-adenosine positive feedback loop. CD73(+) gamma delta Treg infiltration also impaired the tumoricidal functions of CD8(+) T cells and significantly correlated with worse prognosis of patients. The data indicate that the IL6-adenosine loop between CD73(+) gamma delta Tregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy.