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Peer-reviewedCC BY 4.0Cancer Immunology, Immunotherapy : CII

Microbiome-derived TOPOSCORE is associated with response to immune checkpoint inhibitor re-induction after chemotherapy in primary resistant metastatic melanoma

  • Sebastian Haferkamp1,2,3,4
  • Bastian Schilling5
  • Lea Baumgart6
  • Anja Gesierich7
  • Valerie Glutsch7
  • Konstantin Drexler1,3,4
  • Lisa Wein6
  • Monika Morak6
  • Michael Erdmann3,4,8
  • Carola Berking3,4,8
  • Gianmarco Piccinno9
  • Lisa Derosa10,11,12
3 more authors
  • Laurence Zitvogel10,11,12
  • Ying Wang6
  • Lucie Heinzerling3,6,8
12 affiliations
  1. 1Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
  2. 2Department of Dermatology and Venereology, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany
  3. 3Bavarian Cancer Research Center (BZKF), Erlangen, Germany
  4. 4CCC Alliance WERA, Bavaria, Germany
  5. 5Department of Dermatology, Venereology and Allergology, Goethe University Frankfurt, University Hospital, Frankfurt Am Main, Germany
  6. 6Department of Dermatology and Allergy, LMU Medizin, LMU University Hospital, Ludwig-Maximilians-Universität München, Frauenlobstr. 9-11, 80337 Munich, Germany
  7. 7Department of Dermatology, Venereology and Allergology, Bavarian Cancer Research Center (BZKF), University Hospital Würzburg, Würzburg, Germany
  8. 8Department of Dermatology, Deutsches Zentrum Immuntherapie (DZI), CCC Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, Erlangen, Germany
  9. 9Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
  10. 10Clinicobiome, Gustave Roussy, Villejuif, France
  11. 11Université Paris-Saclay, Villejuif, France
  12. 12Équipe Labellisée – Ligue Nationale contre le Cancer, Institut National de La Santé Et de La Recherche Médicale (INSERM) U1015, Villejuif, France
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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.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04618-2.

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Cite

BibTeXRIS
BibTeX
@article{haferkamp2026microbiomederived,
  title = {{Microbiome-derived TOPOSCORE is associated with response to immune checkpoint inhibitor re-induction after chemotherapy in primary resistant metastatic melanoma}},
  author = {Sebastian Haferkamp and Bastian Schilling and Lea Baumgart and Anja Gesierich and Valerie Glutsch and Konstantin Drexler and Lisa Wein and Monika Morak and Michael Erdmann and Carola Berking and Gianmarco Piccinno and Lisa Derosa and Laurence Zitvogel and Ying Wang and Lucie Heinzerling},
  journal = {Cancer Immunology, Immunotherapy : CII},
  year = {2026},
  month = oct,
  doi = {10.1007/s00262-026-04618-2},
  url = {https://doi.org/10.1007/s00262-026-04618-2},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Microbiome-derived TOPOSCORE is associated with response to immune checkpoint inhibitor re-induction after chemotherapy in primary resistant metastatic melanoma
AU  - Sebastian Haferkamp
AU  - Bastian Schilling
AU  - Lea Baumgart
AU  - Anja Gesierich
AU  - Valerie Glutsch
AU  - Konstantin Drexler
AU  - Lisa Wein
AU  - Monika Morak
AU  - Michael Erdmann
AU  - Carola Berking
AU  - Gianmarco Piccinno
AU  - Lisa Derosa
AU  - Laurence Zitvogel
AU  - Ying Wang
AU  - Lucie Heinzerling
PY  - 2026
DA  - 2026/10/30
JO  - Cancer Immunology, Immunotherapy : CII
DO  - 10.1007/s00262-026-04618-2
UR  - https://doi.org/10.1007/s00262-026-04618-2
AB  - 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.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04618-2.
SN  - 0340-7004
SN  - 1432-0851
ER  -