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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
DDR1 functions as an immune negative factor in colorectal cancer by regulating tumor-infiltrating T cells through
Xiaofan Duan1,2, Xiaoxiao Xu1,2, Yumei Zhang1,2
1Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
Discoidin domain receptor 1 (DDR1) hinders anti-cancer immunity in colorectal cancer by reducing T cell infiltration and increasing PD-L1. Targeting DDR1 may improve immunotherapy effectiveness for these patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immunotherapies show promise in cancer treatment but have limited efficacy in most colorectal cancer (CRC) patients.
- Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor overexpressed in malignancies, has an unclear role in CRC and immune regulation.
Purpose of the Study:
- To investigate the role of DDR1 in colorectal cancer progression and its impact on the tumor immune microenvironment.
- To elucidate the underlying mechanisms by which DDR1 influences colorectal cancer growth and immune evasion.
Main Methods:
- Analysis of DDR1 expression in colorectal cancer tissues and correlation with patient survival.
- In vivo studies to assess DDR1's effect on tumor growth.
- Investigation of DDR1's impact on immune cell infiltration (CD4+, CD8+ T cells) and cytokine synthesis (IL-18).
- Exploration of DDR1's effect on PD-L1 expression via the c-Jun amino terminal kinase (JNK) signaling pathway.
Main Results:
- DDR1 is highly expressed in colorectal cancer tissues and associated with poorer patient survival.
- DDR1 promotes colorectal tumor growth specifically in vivo.
- DDR1 acts as a negative immunomodulator, inhibiting CD4+ and CD8+ T cell infiltration by suppressing IL-18 synthesis.
- DDR1 enhances PD-L1 expression through JNK pathway activation.
Conclusions:
- DDR1 plays a significant immunosuppressive role in colorectal cancer.
- DDR1 inhibition represents a potential therapeutic strategy to enhance immunotherapy efficacy in colorectal cancer patients.
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