The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China.
Int J Cancer. 2019 Oct 15;145(8):2225-2237. doi: 10.1002/ijc.32355. Epub 2019 May 6.
Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor protein and highly expressed in myeloid cells. Our previous study demonstrates a critical protective effect of CARD9 in the development of colitis-associated colon cancer. Nevertheless, the effect of CARD9 in lung cancer remains unclear. Here, using a mouse Lewis lung cancer model, we found the tumor burden of CARD9 mice was much heavier than that in wild-type (WT) mice. More myeloid-derived suppressor cells (MDSCs) were accumulated and less cytotoxicity T lymphocyte was found in tumor tissues of CARD9 mice, compared to WT mice. Depleting MDSCs using anti-Gr1 antibody can significantly decrease tumor burden in CARD9 mice. Furthermore, the noncanonical nuclear factor-kappaB (NF-κB) pathway was activated in CARD9 mice-derived MDSCs. Deficiency of CARD9 enhanced expression of indoleamine 2,3-dioxygenase (IDO) in MDSCs via noncanonical NF-κB pathway. Moreover, correlations between CARD9 expressions and MDSCs relative genes (IDO, iNOS-2 and arginase 1 [ARG-1]) were further confirmed in tumor tissues from lung cancer patients. Taken together, we showed a CARD9-NF-κB-IDO pathway in MDSCs which can inhibit the suppressive function of MDSCs and prevent lung cancer development.
Caspase recruitment domain-containing protein 9 (CARD9) 是一种衔接蛋白，在髓系细胞中高度表达。我们之前的研究表明 CARD9 在结肠炎相关结肠癌的发生发展中具有关键的保护作用。然而，CARD9 在肺癌中的作用尚不清楚。在这里，我们使用小鼠 Lewis 肺癌模型发现，CARD9 小鼠的肿瘤负担比野生型（WT）小鼠重得多。与 WT 小鼠相比，CARD9 小鼠的肿瘤组织中积聚了更多的髓系来源的抑制细胞（MDSCs），而细胞毒性 T 淋巴细胞较少。使用抗 Gr1 抗体耗尽 MDSCs 可显著降低 CARD9 小鼠的肿瘤负担。此外，CARD9 小鼠来源的 MDSCs 中激活了非经典核因子-κB（NF-κB）通路。CARD9 缺陷通过非经典 NF-κB 通路增强了 MDSCs 中吲哚胺 2,3-双加氧酶（IDO）的表达。此外，在肺癌患者的肿瘤组织中进一步证实了 CARD9 表达与 MDSCs 相关基因（IDO、iNOS-2 和精氨酸酶 1 [ARG-1]）之间的相关性。综上所述，我们在 MDSCs 中发现了一条 CARD9-NF-κB-IDO 通路，该通路可以抑制 MDSCs 的抑制功能，从而预防肺癌的发生。
