Matilda Doran

Clinical responses to immune checkpoint inhibitors (ICIs) targeting CD8+ T cells are variable; approximately half of stage III/IV melanoma patients fail to respond to these drugs or maintain long-term control. Gut microbiota modulate ICI responsiveness however, specific bacterial species associated with clinical benefit are inconsistent across studies, presenting a barrier to clinical translation.

There is evidence that microbial metabolites are a key mechanism by which gut microbiota regulate T cell immunity against melanoma. To identify additional metabolites associated with treatment outcome, we performed metagenomic sequencing of stool samples from stage III/IV melanoma patients treated with ICIs. This identified several candidate metabolites associated with ICI efficacy, including choline.

Choline is a semi-essential nutrient predominantly obtained through diet. It is metabolised by the host and by the gut microbiota to generate distinct products with diverse roles throughout the body.

However, microbiota-derived choline metabolites remain poorly characterised in the context of stem-like CD8+ T cells and melanoma.

Using flow cytometry, we found that choline exposure increased mitochondrial oxidation and enhanced numbers of CD8+ T cells in an in vivo challenge model, whilst dietary choline supplementation augmented CD8+ T cell abundance.

Together, these data indicate that microbial choline derivatives can modify CD8+ T cell metabolism and expansion, making them a promising target to modulate T cell immunity against melanoma. Our findings suggest that manipulation of choline‑related pathways through diet, microbiota‑targeted interventions, or defined microbial consortia could be leveraged to improve the efficacy and durability of ICI therapy in melanoma patients.