CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer
CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer
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DOI：
10.1038/s41598-020-63482-x
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发表时间：
2020-04-16
影响因子：
4.6
通讯作者：
Pioli, Patricia A.
中科院分区：
文献类型：
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作者：
Ball, Michael S.;Bhandari, Rajan;Pioli, Patricia A.
肿瘤微环境(TME)是恶性肿瘤发生发展的重要因素。在TME内，肿瘤相关巨噬细胞(TAMs)介导血管生成、转移和免疫抑制，从而抑制肿瘤特异性细胞毒CD8+T细胞的渗透。在以前的工作中，我们在体外证明了合成的三萜类CDDO-甲酯(CDDO-Me)可以将乳腺TAMs从促进肿瘤转化为抑制肿瘤激活状态。我们现在发现，CDDO-Me重塑了乳房的TME，重定向了的激活和体内T细胞肿瘤的侵袭。我们证明，CDDO-Me显著降低IL-10和VEGF的表达，但刺激肿瘤坏死因子的产生，并减少免疫抑制TAM的标志物CD206和CD115的表面表达。CDDO-Me治疗改变了的转录水平，诱导了与免疫刺激相关的信号通路，并抑制了肿瘤的侵袭，与CCL2表达减少一致。CDDO-Me处理组小鼠脾组织中CD4(+)T细胞的绝对数和比例均降低，而肿瘤和脾组织中CD8(+)T细胞的比例均显著升高。此外，喂食CDDO-Me的小鼠显示出肿瘤内CD4(+)Foxp3(+)调节性T细胞的数量显著减少。这些结果首次证明，CDDO-Me缓解了乳房TME中的免疫抑制，并释放了宿主适应性抗肿瘤免疫。
The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro. We show now that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of splenic CD4(+) T cells were reduced, while the proportion of CD8(+) T cells was significantly increased in both tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of CD4(+) Foxp3(+) regulatory T cells within tumors. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast TME and unleashes host adaptive anti-tumor immunity.