In B16F10 tumor-bearing mice, ICB (anti-PD-1 + anti-CTLA-4) increased the quantity of bacteria in GI tract-draining mesenteric lymph nodes (mLNs), tumor-draining LNs, spleens, and tumors and were enriched in specific taxa with DC-activating potential. Gut bacteria distribution after ICB was driven not by disruption of gut epithelium, but instead by DC trafficking (CD11c- and CCR7-dependent) and mLN remodeling (expanded HEVs and lymphangiogenesis). mLN resection or antibiotic administration prior to ICB reduced LN bacterial load and effector T cell proportion, disrupting antitumor efficacy. Administration of beneficial taxa improved ICB outcomes.
Contributed by Alex Najibi
ABSTRACT: Gut microbiota, specifically gut bacteria, are critical for effective immune checkpoint blockade therapy (ICT) for cancer. The mechanisms by which gut microbiota augment extraintestinal anticancer immune responses, however, are largely unknown. Here, we find that ICT induces the translocation of specific endogenous gut bacteria into secondary lymphoid organs and subcutaneous melanoma tumors. Mechanistically, ICT induces lymph node remodeling and dendritic cell (DC) activation, which facilitates the translocation of a selective subset of gut bacteria to extraintestinal tissues to promote optimal antitumor T cell responses in both the tumor-draining lymph nodes (TDLNs) and the primary tumor. Antibiotic treatment results in decreased gut microbiota translocation into mesenteric lymph nodes (MLNs) and TDLNs, diminished DC and effector CD8(+) T cell responses, and attenuated responses to ICT. Our findings illuminate a key mechanism by which gut microbiota promote extraintestinal anticancer immunity.
Author Info: (1) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Immunology, University of Texas
Author Info: (1) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (2) Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (3) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (4) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (5) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (6) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Cell and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (7) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (8) Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (9) Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (10) Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (11) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (12) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (13) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (14) Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center Cincinnati, Cincinnati, OH 45229, USA. Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45220, USA. (15) Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
