DDR1 functions as an immune negative factor in colorectal cancer by regulating tumor-infiltrating T cells through IL-18,Cancer Science

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DDR1 functions as an immune negative factor in colorectal cancer by regulating tumor-infiltrating T cells through IL-18
Cancer Science ( IF 4.5 ) Pub Date : 2022-08-15 , DOI: 10.1111/cas.15533
Xiaofan Duan _{1,

2} , Xiaoxiao Xu _{1,

2} , Yumei Zhang _{1,

2} , Yuan Gao _{1,

2} , Jiuli Zhou ₁ , Jin Li ₁

Affiliation

Immunotherapies represented by programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors have made great progress in the field of anticancer treatment, but most colorectal cancer patients do not benefit from immunotherapy. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, is activated by collagen binding and overexpressed in various malignancies. However, the role of DDR1 in colorectal cancer and immunoregulation remains unclear. In this study, we found DDR1 is highly expressed in colorectal cancer tissues and negatively associated with patient survival. We demonstrated that DDR1 promotes colorectal tumor growth only in vivo. Mechanistically, DDR1 is a negative immunomodulator in colorectal cancer and is involved in low infiltration of CD4⁺ and CD8⁺ T cells by inhibiting IL-18 synthesis. We also reported that DDR1 enhances the expression of PD-L1 through activating the c-Jun amino terminal kinase (JNK) signaling pathway. In conclusion, our findings elucidate the immunosuppressive role of DDR1 in colorectal cancer, which may represent a novel target to enhance the efficacy of immunotherapy in colorectal cancer.

中文翻译：

DDR1 通过 IL-18 调节肿瘤浸润性 T 细胞，在结直肠癌中发挥免疫负性因子的作用

以程序性细胞死亡蛋白1/程序性细胞死亡配体1（PD-1/PD-L1）免疫检查点抑制剂为代表的免疫疗法在抗癌治疗领域取得了长足的进步，但大多数结直肠癌患者并没有从免疫疗法中获益。盘状蛋白结构域受体 1 (DDR1) 是一种酪氨酸激酶受体，被胶原蛋白结合激活并在各种恶性肿瘤中过度表达。然而，DDR1在结直肠癌和免疫调节中的作用仍不清楚。在这项研究中，我们发现 DDR1 在结直肠癌组织中高度表达，并且与患者生存率呈负相关。我们证明 DDR1 仅在体内促进结直肠肿瘤的生长。机制上，DDR1 是结直肠癌的负性免疫调节剂，参与 CD4 ⁺和 CD8的低浸润⁺ T 细胞通过抑制 IL-18 合成。我们还报道了 DDR1 通过激活 c-Jun 氨基末端激酶 (JNK) 信号通路来增强 PD-L1 的表达。总之，我们的研究结果阐明了 DDR1 在结直肠癌中的免疫抑制作用，这可能代表了增强结直肠癌免疫治疗疗效的新靶点。

更新日期：2022-08-15

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