Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer
Seung Yoon Lee,
JooYeon Jhun,
Jin Seok Woo,
Kun Hee Lee,
Sun-Hee Hwang,
Jeonghyeon Moon,
Goeun Park,
Sun Shim Choi,
So Jung Kim,
Yoon Ju Jung,
Kyo Young Song,
Mi-La Cho
Affiliations
Seung Yoon Lee
Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
JooYeon Jhun
Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
Jin Seok Woo
Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
Kun Hee Lee
Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
Sun-Hee Hwang
Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
Jeonghyeon Moon
Departments of Immunobiology and Neurology, Yale School of Medicine, New Haven, CT, USA
Goeun Park
Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, Korea
Sun Shim Choi
Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, Korea
So Jung Kim
Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Yoon Ju Jung
Division of Gastrointestinal Surgery, Department of Surgery, Yeouido St. Mary’s Hospital, Seoul, Korea
Kyo Young Song
Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Mi-La Cho
Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
ABSTRACTEarly 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.
