Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer

ABSTRACT

Early detection and surgical treatment are essential to achieve a good outcome in gastric cancer (GC). Stage IV and recurrent GC have a poor prognosis. Therefore, new treatments for GC are needed. We investigated the intestinal microbiome of GC patients and attempted to reverse the immunosuppression of the immune and cancer cells of GC patients through the modulation of microbiome metabolites. We evaluated the levels of programmed death-ligand 1 (PD-L1) and interleukin (IL)-10 in the peripheral blood immunocytes of GC patients. Cancer tissues were obtained from patients who underwent surgical resection of GC, and stained sections of cancer tissues were visualized via confocal microscopy. The intestinal microbiome was analyzed using stool samples of healthy individuals and GC patients. Patient-derived avatar model was developed by injecting peripheral blood mononuclear cells (PBMCs) from advanced GC (AGC) patients into NSG mice, followed by injection of AGS cells. PD-L1 and IL-10 had higher expression levels in immune cells of GC patients than in those of healthy controls. The levels of immunosuppressive factors were increased in the immune and tumor cells of tumor tissues of GC patients. The abundances of Faecalibacterium and Bifidobacterium in the intestinal flora were lower in GC patients than in healthy individuals. Butyrate, a representative microbiome metabolite, suppressed the expression levels of PD-L1 and IL-10 in immune cells. In addition, the PBMCs of AGC patients showed increased levels of immunosuppressive factors in the avatar mouse model. Butyrate inhibited tumor growth in mice. Restoration of the intestinal microbiome and its metabolic functions inhibit tumor growth and reverse the immunosuppression due to increased PD-L1 and IL-10 levels in PBMCs and tumor cells of GC patients.

KEYWORDS:

• Gastric cancer
• PD-L1
• IL-10
• microbiome
• butyrate
• avatar model
• Faecalibacterium prausnitzii

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1F1A1073227) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HV22C0069).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conception and design: K.Y.S. and M.L.C; Analysis and interpretation of the data: S.Y.L. J.J., K.H.L., J.S.W., S.H.H., S.J.K., and Y.J.J; Drafting of the article: S.Y.L., J.J., J.S.W., and Y.J.J.; Editing manuscript: K.Y.S. and M.L.C. All authors have approved the final version of the manuscript. K.Y.S. and M.L.C. takes responsibility for the integrity of the work in its entirety.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article. Gut microbiome analysis was deposited in the BioProject and Sequence Read Archive (SRA; https://www.ncbi.nlm.nih.gov/sra) under the accession numbers PRJNA937852.

Ethics approval and consent to participate

All the procedures were approved by the Animal Research Ethics Committee of the Catholic University of Korea (CUCM-2021–0333–05) and the institutional Review Board of the college of Medicine, Catholic University of Korea (IRB No. KC20TISI0985)

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2300846

Additional information

Funding

This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2023R1A2C1003867).