Targeted DDR1 Treatment Strategy Enhances PD-1 Immunotherapy Efficacy against Gastric Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Advanced gastric cancer (GC) often shows resistance to current immunotherapy treatments.
• Discoidin domain receptor 1 (DDR1) plays a crucial role in tumor-stroma interactions and creates an immunosuppressive tumor microenvironment.
• High DDR1 expression correlates with poor prognosis in gastric cancer patients.

Purpose of the Study:

• To investigate the therapeutic potential of targeting DDR1 in advanced gastric cancer.
• To develop and evaluate a DDR1-targeting monoclonal antibody (mAb) for gastric cancer treatment.
• To elucidate the mechanisms by which DDR1 inhibition impacts tumor progression and the immune microenvironment.

Main Methods:

• Multiomics analysis to associate DDR1 expression with GC prognosis and immunosuppression.
• Genetic knockdown of DDR1 to assess its role in tumor progression.
• Development of a DDR1-targeting monoclonal antibody (mAb).
• In vivo studies using murine models to evaluate the efficacy of anti-DDR1 mAb in combination with anti-PD-1 therapy.
• Mechanistic studies to determine how the mAb interacts with DDR1 and affects downstream signaling pathways (Col1-DDR1-ERK) and immune cell recruitment (CD8+ T cells).

Main Results:

• High DDR1 expression was linked to poor prognosis and an immunosuppressive tumor microenvironment in GC.
• Genetic DDR1 knockdown demonstrated its importance in inhibiting tumor progression.
• The anti-DDR1 mAb synergized with anti-PD-1 therapy in murine models, significantly suppressing tumor growth and improving survival.
• The mAb binds to the DDR1 DS-DS-like-EJM domain, inhibiting collagen I interaction and blocking the Col1-DDR1-ERK pathway.
• The mAb demonstrated dual immune-activating effects, including antibody-dependent cellular cytotoxicity (ADCC)/complement-dependent cytotoxicity (CDC) and enhanced recruitment/cytotoxicity of CD8+ T cells via CCL3/CXCL11 upregulation.

Conclusions:

• DDR1 inhibition is a promising multimodal strategy for gastric cancer treatment.
• Targeting DDR1 can convert immunologically "cold" tumors into more responsive ones.
• The combination of DDR1 blockade with PD-1 inhibitors represents a novel and potentially effective therapeutic approach for advanced gastric cancer.