Steroid receptor coactivator-3 inhibition generates breast cancer antitumor immune microenvironment.
Steroid receptor coactivator-3 inhibition generates breast cancer antitumor immune microenvironment.
复制标题
DOI：
10.1186/s13058-022-01568-2
复制
发表时间：
2022-10-31
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
肿瘤免疫环境（时间）是通过癌症浸入癌症在促进或抑制乳腺癌进展中的至关重要的作用。乳腺癌的模型。
我们在免疫单与雌性C57BL/6和BALB/C小鼠中使用E0771和4T1乳腺癌。 RC-3 KD-4T1细胞及其亲本乳腺癌细胞被注入其合成性免疫直立的雌性小鼠与免疫缺陷小鼠验证宿主免疫系统是否在免疫直觉小鼠中被src-3 kd抑制乳腺肿瘤需要71和4T1乳腺癌是通过免疫组织化学确定的。用小鼠细胞因子阵列定义了经SI-2处理和SRC-3 KD E0771乳腺肿瘤及其对照癌的细胞因子水平。
SI-2的SRC-3抑制作用显着抑制了乳腺癌细胞的进展（E0771和4T1）在免疫独立性雌性小鼠中抑制乳腺癌的乳腺癌，SRC-3 KD-E0771和-4T1乳腺癌细胞中的乳腺癌细胞良好，但SRC-3 KD-E0771和-4T1 o缺陷的宿主小鼠。 KD有效地增加了细胞毒性细胞的数量，例如CD4+和CD8+ T细胞和CD56+ NK细胞的数量，而乳腺癌中的干扰素γ（IFNG）与媒介物相比，与车辆相比，SI-2的数量降低了肿瘤侵蚀的数量。 -c基序趋化因子配体9 （CXCL9）在乳腺癌中的表达募集C-X-C基序趋化因子受体3（CXCR3）表达细胞毒性免疫细胞中乳腺肿瘤的表达。
SRC-3是乳腺癌中的关键免疫调节剂，产生病免疫微环境，SI-2或SRC-3 KD抑制SRC-3。
在线版本包含的补充材料可获得10.1186/S13058-022-01568-2。
The tumor immune microenvironment (TIME) generated by cancer-infiltrating immune cells has a crucial role in promoting or suppressing breast cancer progression. However, whether the steroid receptor coactivator-3 (SRC-3) modulates TIME to progress breast cancer is unclear. Therefore, the present study evaluates whether SRC-3 generates a tumor-promoting TIME in breast tumors using a syngeneic immune-intact mouse model of breast cancer. We employed E0771 and 4T1 breast cancer in immune-intact syngeneic female C57BL/6 and BALB/c mice, respectively. SI-2, a specific small-molecule inhibitor of SRC-3, was administered daily (2.5 mg/kg) to E0771 and 4T1 breast tumor-bearing immune-intact mice. In addition, SRC-3 knockdown (KD)-E0771 and SRC-3 KD-4T1 cells and their parental breast cancer cells were injected into their syngeneic immune-intact female mice versus immune-deficiency mice to validate that the host immune system is required for breast tumor suppression by SRC-3 KD in immune-intact mice. Furthermore, tumor-infiltrating immune cells (such as CD4+, CD8+, CD56+, and Foxp3+ cells) in E0771 and 4T1 breast cancers treated with SI-2 and in SRC-3 KD E0771 and 4T1 breast cancers were determined by immunohistochemistry. Additionally, cytokine levels in SI-2-treated and SRC-3 KD E0771 breast tumors and their control cancers were defined with a Mouse Cytokine Array. SRC-3 inhibition by SI-2 significantly suppressed the progression of breast cancer cells (E0771 and 4T1) into breast cancers in immune-intact syngeneic female mice. SRC-3 KD-E0771 and -4T1 breast cancer cells did not produce well-developed tumors in immune-intact syngeneic female mice compared to their parental cells, but SRC-3 KD breast cancers were well developed in immune-defective host mice. SRC-3 inhibition by SI-2 and SRC-3 KD effectively increased the numbers of cytotoxic immune cells, such as CD4+ and CD8+ T cells and CD56+ NK cells, and Interferon γ (Ifng) in breast cancers compared to vehicle. However, SI-2 treatment reduced the number of tumor-infiltrating CD4+/Foxp3+ regulatory T (Treg) cells compared to vehicle treatment. In addition, SRC-3 inhibition by SI-2 and SRC-3 KD increased C-X-C motif chemokine ligand 9 (Cxcl9) expression in breast cancer to recruit C-X-C motif chemokine receptor 3 (Cxcr3)-expressing cytotoxic immune cells into breast tumors. SRC-3 is a critical immunomodulator in breast cancer, generating a protumor immune microenvironment. SRC-3 inhibition by SI-2 or SRC-3 KD activates the Cxcl9/Cxcr3 axis in breast tumors and enhances the antitumor immune microenvironment to suppress breast cancer progression. The online version contains supplementary material available at 10.1186/s13058-022-01568-2.
登录
查看更多内容
影响因子：
32.4
作者：
Hill, Jonathan A.;Feuerer, Markus;Benoist, Christophe
通讯作者：
Benoist, Christophe
影响因子：
4.6
作者：
Guo B;Fu S;Zhang J;Liu B;Li Z
通讯作者：
Li Z
影响因子：
10.5
作者：
Dasgupta S;Lonard DM;O'Malley BW
通讯作者：
O'Malley BW
影响因子：
4.6
作者：
Gilad, Yosi;Eliaz, Yossi;Lonard, David M.
通讯作者：
Lonard, David M.
影响因子：
2.3
作者：
Conlon, Kevin C.;Miljkovic, Milos D.;Waldmann, Thomas A.
通讯作者：
Waldmann, Thomas A.