Reduced Number and Immune Dysfunction of CD4+ T Cells in Obesity Accelerate Colorectal Cancer Progression
Kota Yamada,
Masafumi Saito,
Masayuki Ando,
Tomoki Abe,
Tomosuke Mukoyama,
Kyosuke Agawa,
Akihiro Watanabe,
Shiki Takamura,
Mitsugu Fujita,
Naoki Urakawa,
Hiroshi Hasegawa,
Shingo Kanaji,
Takeru Matsuda,
Taro Oshikiri,
Yoshihiro Kakeji,
Kimihiro Yamashita
Affiliations
Kota Yamada
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Masafumi Saito
Department of Disaster and Emergency and Critical Care Medicine, Graduate School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
Masayuki Ando
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Tomoki Abe
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Tomosuke Mukoyama
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Kyosuke Agawa
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Akihiro Watanabe
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Shiki Takamura
Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ono-higashi, Osakasayama 589-0014, Japan
Mitsugu Fujita
Center for Medical Education and Clinical Training, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osaka 589-0014, Japan
Naoki Urakawa
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Hiroshi Hasegawa
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Shingo Kanaji
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Takeru Matsuda
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Taro Oshikiri
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Yoshihiro Kakeji
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Kimihiro Yamashita
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan
Obesity, a known risk factor for various types of cancer, reduces the number and function of cytotoxic immune cells in the tumor immune microenvironment (TIME). However, the impact of obesity on CD4+ T cells remains unclear. Therefore, this study aimed to clarify the impact of obesity on CD4+ T cells in the TIME. A tumor-bearing obese mouse model was established by feeding with 45% high-fat diet (HFD), followed by inoculation with a colon cancer cell line MC38. Tumor growth was significantly accelerated compared to that in mice fed a control diet. Tumor CD4+ T cells showed a significant reduction in number and an increased expression of programmed death-1 (PD-1), and decreased CD107a expression and cytokine such as IFN-γ and TNF-α production, indicating dysfunction. We further established CD4+ T cell-depleted HFD-fed model mice, which showed reduced tumor infiltration, increased PD-1 expression in CD8+ T cells, and obesity-induced acceleration of tumor growth in a CD4+ T cell-dependent manner. These findings suggest that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells to ultimately accelerate the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity.
