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Koumine alters immune barrier function by targeting TGFβ-mediated collagen deposition in gastric cancer
Hailing Lin1, Jingping Liu1, Yuli Tang2
1Department of Pharmacy, Fujian Medical University Union Hospital, 29 Xin Quan Rd, Gulou, Fuzhou, 350001, PR China.
Abstract:
Gastric cancer (GC) is one among the most fatal cancers worldwide. Although immunotherapy has expanded the treatment options for patients with advanced GC, the immunosuppressive tumor microenvironment (TME) of GC renders it resistant to immunotherapy. This underscores the urgent need for strategies to enhance the efficacy of immunotherapies. In this study, we identified a natural compound Koumine, which suppresses GC cancer growth in vivo, however, not in vitro. Koumine markedly reduced collagen (COL21A1, COL3A1, COL13A1, and COL14A1) expression in GC cells and significantly increased T-cell infiltration into the tumors. Mechanistically, Koumine was observed to directly bind to and inhibit the kinase activity of transforming growth factor beta receptor 1 (TGFβR1), thereby suppressing Smad2/3 signaling, which led to the downregulation of collagen proteins and increased anti-tumor immunity. Furthermore, the combination of Koumine with anti-PD1 immune checkpoint inhibitor generated synergistic effects in immune-competent GC mouse models, enhancing CD8+ T-cell infiltration and significantly inhibiting tumor growth. The results of our study suggest that Koumine is a potent agent that may be used to disrupt immune exclusion and optimize immunotherapy in patients with GC.
Insights
Koumine, a natural compound, inhibits gastric cancer growth by reducing collagen and increasing T-cell infiltration. Combining Koumine with anti-PD1 therapy shows synergistic effects, enhancing anti-tumor immunity for gastric cancer treatment.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Gastric cancer (GC) is a leading cause of cancer death globally.
- The immunosuppressive tumor microenvironment (TME) limits immunotherapy efficacy in GC.
- Novel strategies are needed to overcome GC's resistance to immunotherapy.
Purpose of the Study:
- To investigate the anti-cancer effects of the natural compound Koumine in gastric cancer.
- To elucidate the mechanism of Koumine's action on the tumor microenvironment.
- To evaluate the therapeutic potential of Koumine in combination with immunotherapy.
Main Methods:
- In vivo and in vitro studies of Koumine on GC cell growth.
- Analysis of collagen expression and T-cell infiltration in GC models.
- Investigation of Koumine's interaction with transforming growth factor beta receptor 1 (TGFβR1) signaling.
- Combination therapy studies with Koumine and anti-PD1 immune checkpoint inhibitors in mice.
Main Results:
- Koumine suppressed GC tumor growth in vivo but not in vitro.
- Koumine reduced collagen expression (COL21A1, COL3A1, COL13A1, COL14A1) and increased T-cell infiltration.
- Koumine directly inhibited TGFβR1 kinase activity, suppressing Smad2/3 signaling.
- Combination therapy with Koumine and anti-PD1 demonstrated synergistic anti-tumor effects, increasing CD8+ T-cell infiltration.
Conclusions:
- Koumine effectively suppresses gastric cancer growth and enhances anti-tumor immunity.
- Koumine disrupts the immunosuppressive TME by downregulating collagen and increasing T-cell infiltration.
- Koumine holds promise as an adjuvant therapy to improve immunotherapy outcomes in gastric cancer patients.
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