Oral Presentation Melbourne Immunotherapy Spring Symposium 2025

SCFA producing capabilities of the gut microbiota enhance tumor-specific CD127+CD8+ T cell immunity against melanoma   (127151)

Annabell Bachem 1 , Michele Clarke 1 , Geraldine Kong 1 , Lindsay Kosack 1 , Kah Min Yap 2 , Kshitij Tandon 1 , Vanessa R Marcelino 1 , Paul Beavis 2 , Shahneen Sandhu 3 , Thomas Gebhardt 1 , Sammy Bedoui 1
  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunology, The University of Melbourne, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Gut microbiota modulate cancer control but how the different bacteria impact tumor-specific CD8+ T cell immunity remains unclear. Here, we identified that spontaneous control of cutaneous melanoma in mice correlated with microbiome-encoded metabolic pathways required for short-chain fatty acid (SCFA) synthesis. Diet-induced enforcement of microbial SCFA production reduced tumor progression and enriched tumor-specific CD8+ T cells in the tumor draining lymph node (tdLN) that lacked features of exhausted T cells. The SCFA butyrate promoted a FOXO1-dependent stemness program in these CD8+ T cells, enhanced the differentiation of CD127+CD8+ T cells and induced immune checkpoint blockade (ICB) responsiveness. Consistent with these experimental studies, metabolic modelling predicted enhanced microbial production of the SCFA butyrate in ICB-responsive melanoma patients and butyrate induced transcriptional features of ICB-responsiveness in CD8+ T cells. Collectively, these data identify the effects of microbial metabolic pathways on tumor-specific CD8+ T cell differentiation as critical components of how the gut microbiome regulates cancer immunity.