Cancer Immunol Immunother. 2026 Oct 30;75(11):265. doi: 10.1007/s00262-026-04618-2.
ABSTRACT
BACKGROUND: Primary resistance to immune checkpoint inhibitors (ICIs) remains a major challenge in metastatic melanoma. The prospective multicenter PROMIT trial showed that intermittent chemotherapy could restore sensitivity to ICI re-induction in a subset of patients. We investigated whether gut microbiome ecosystem states characterized by TOPOSCORE were associated with tumor response in this setting.
METHODS: In the phase II PROMIT trial (NCT04225390), 24 patients with longitudinal stool samples were included in this exploratory microbiome analysis. ICI-resistant patients received two cycles of dacarbazine followed by ICI re-induction. Stool samples underwent shotgun metagenomic sequencing. Microbiome ecosystem states were classified into SIG1- or SIG2-associated ecosystem states using the TOPOSCORE framework, which is based on species-interacting groups (SIGs) defined by ecological co-abundance patterns.
RESULTS: Baseline TOPOSCORE distributions and s-scores were not associated with clinical outcome. In the nine patients with complete BL-CTX-ICI sampling, six retained the same TOPOSCORE category throughout treatment and three changed category. Of the two patients with PR, one remained SIG2 throughout, whereas the other changed from SIG2+ to SIG1+ after chemotherapy and returned to SIG2+ during ICI re-induction. Analyses using all available samples at each phase likewise did not show significant differences in s-score among PR, SD, and PD groups.
CONCLUSIONS: Baseline TOPOSCORE classification was insufficient to predict treatment outcome in this cohort. Longitudinal TOPOSCORE patterns were heterogeneous, and the small number of complete longitudinal profiles precludes conclusions that chemotherapy induced a favorable microbiome transition. These exploratory findings support further evaluation of microbiome ecosystem dynamics in larger prospective cohorts.
PMID:42965706 | DOI:10.1007/s00262-026-04618-2
