Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance.
Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance.
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DOI：
10.1158/0008-5472.can-15-2654
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发表时间：
2016-06-01
期刊：
影响因子：
11.2
通讯作者：
Upadhyay G
中科院分区：
文献类型：
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作者：
AlHossiny M;Luo L;Frazier WR;Steiner N;Gusev Y;Kallakury B;Glasgow E;Creswell K;Madhavan S;Kumar R;Upadhyay G
干细胞抗原Sca-1与小鼠癌症干细胞生物学和乳腺癌模型有关，但其人类同源物Ly 6 K和Ly 6 E在乳腺癌中的作用尚未确定。在这里，我们报告了Ly 6 K/E在人乳腺癌标本中的表达增加与总生存率差相关，Ly 6 E在治疗效果差中具有额外的特定作用。Ly 6 K/E的表达增加还与免疫检查点分子PDL 1和CTLA 4的表达增加、肿瘤浸润性T调节细胞增加和自然杀伤（NK）细胞活化减少相关。从机制上讲，Ly 6 K/E是乳腺癌细胞中TGF-β信号传导和增殖所必需的，它们有助于Smad 1/5和Smad 2/3的磷酸化。此外，Ly 6 K/E促进了精氨酸诱导的PDL 1表达以及NK细胞与癌细胞的活化和结合。最后，我们发现Ly 6 K/E在这种情况下促进耐药性并促进免疫逃逸。总的来说，我们的结果确立了涉及TGF-β的Ly 6 K/E信号传导轴在乳腺癌病理生理学和药物反应中的关键作用，并强调了该信号传导轴作为治疗发明的引人注目的领域。
Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologues Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E were required for TGF-β signaling and proliferation in breast cancer cells where they contributed to phosphorylation of Smad1/5 and Smad2/3. Further, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Lastly, we found that Ly6K/E promoted drug resistance and facilitate immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGF-β in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention.