Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Tongji University School of Medicine, Shanghai, China.
Cancer Sci. 2022 Nov;113(11):3672-3685. doi: 10.1111/cas.15533. Epub 2022 Aug 24.
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.
免疫疗法代表着程序性死亡蛋白 1/程序性死亡配体 1（PD-1/PD-L1）免疫检查点抑制剂在抗肿瘤治疗领域取得了重大进展，但大多数结直肠癌患者不能从中受益。黏着斑激酶受体 1（DDR1）是一种酪氨酸激酶受体，通过与胶原结合而被激活，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尚不清楚。在这项研究中，我们发现 DDR1 在结直肠癌组织中高表达，与患者的生存呈负相关。我们证明 DDR1 仅在体内促进结直肠肿瘤的生长。从机制上讲，DDR1 是结直肠癌的一种负免疫调节剂，通过抑制白细胞介素 18 的合成，参与 CD4 和 CD8 T 细胞的低浸润。我们还报告称，DDR1 通过激活 c-Jun 氨基末端激酶（JNK）信号通路，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，这可能代表了一个增强结直肠癌免疫治疗疗效的新靶点。
