Interleukin 27 protects from gastric atrophy and metaplasia during chronic autoimmune gastritis

BACKGROUND & AIMS: The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. METHODS: We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3 RESULTS: We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. CONCLUSIONS: In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa

Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk

Obesity is a well-established risk factor for human cancer, yet the underlying mechanisms remain elusive. Immune dysfunction is commonly associated with obesity but whether compromised immune surveillance contributes to cancer susceptibility in individuals with obesity is unclear. Here we use a mouse model of diet-induced obesity to investigate tumor-infiltrating CD8 + T cell responses in lean, obese, and previously obese hosts that lost weight through either dietary restriction or treatment with semaglutide. While both strategies reduce body mass, only dietary intervention restores T cell function and improves responses to immunotherapy. In mice exposed to a chemical carcinogen, obesity-related immune dysfunction leads to higher incidence of sarcoma development. However, impaired immunoediting in the obese environment enhances tumor immunogenicity, making the malignancies highly sensitive to immunotherapy. These findings offer insight into the complex interplay between obesity, immunity and cancer, and provide explanation for the obesity paradox observed in clinical immunotherapy settings

Figure S7 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

IL-15 significantly improves activation of sip-T in peripheral blood in vivo</p

Supplementary Tables 1-7 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

Supplementary Tables 1-7</p

Figure S5 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

IL-15 expands antigen-specific T-cell subsets of sip-T</p

Figure S1 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

Swimmer plots and PSA levels</p

Figure S6 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

CD8+ T-cell and CD56+ NK/T cells are the primary source of IL-15-mediated enhancement of sip-T efficacy</p

Figure S3 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

IL-15 dose response in sipuleucel-T</p

Figure S8 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

IL-15 significantly improves sip-T mediated suppression of tumor growth in vivo</p

Figure S12 from High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance

Correlation plots between clinical outcomes and sip-T subsets</p