Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy
7 affiliations
- 1Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- 2Department of Pathology, University Hospital Basel, Basel, Switzerland
- 3Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
- 4Innovation Focus Cell Therapies, University Hospital Basel, Basel, Switzerland
- 5Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel and University of Basel, Basel, Switzerland
- 6Division of Hematology, University Hospital Basel, Basel, Switzerland
- 7Division of Infectious Diseases, University Hospital Basel, Basel, Switzerland
Abstract
Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) induces durable responses in metastatic melanoma, yet the clonal and transcriptional dynamics governing tumor-reactive T cell fate during ex vivo expansion and after transfer remain poorly understood. Here, we perform longitudinal single-cell RNA and T cell receptor sequencing across five time points, from baseline tumors through two-phase ex vivo expansion to post-infusion blood and tumor biopsies, in seven melanoma patients, resolving both the CD8+ and CD4+ compartments. Tumor-reactive CD8+ T cells are reinvigorated from exhaustion and acquire HLA-II-high or KLF2-high profiles. We further dissect the tumor-responsive CD4+ compartment in depth, revealing lineage-dependent reinvigoration in which follicular helper T cells adopt an effector state while exhausted CD4+ T cells retain dysfunction. In non-responders, across three cohorts, co-transferred type 17 T cells and de novo regulatory T cell expansion after transfer associate with treatment failure. These data define subtype-specific signatures across both lineages to guide TIL expansion.
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BibTeX
@article{sandholzer2026singlecell,
title = {{Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy}},
author = {Michael T. Sandholzer and Clara Serger and Alessia G. Liner and Sarp Uzun and David König and Helen Thut and Reto Ritschard and Jonas D. Fürst and Andreas Zingg and Natalia Rodrigues Mantuano and Benjamin Kasenda and Katharina Glatz and Elisabeth A. Kappos and Matthias Matter and Andreas Holbro and Frank Stenner and Jakob Passweg and Nina Khanna and Lukas Jeker and Mascha Binder and Alfred Zippelius and Heinz Läubli},
journal = {Cell Reports Medicine},
year = {2026},
month = sep,
doi = {10.1016/j.xcrm.2026.103051},
url = {https://doi.org/10.1016/j.xcrm.2026.103051},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy
AU - Michael T. Sandholzer
AU - Clara Serger
AU - Alessia G. Liner
AU - Sarp Uzun
AU - David König
AU - Helen Thut
AU - Reto Ritschard
AU - Jonas D. Fürst
AU - Andreas Zingg
AU - Natalia Rodrigues Mantuano
AU - Benjamin Kasenda
AU - Katharina Glatz
AU - Elisabeth A. Kappos
AU - Matthias Matter
AU - Andreas Holbro
AU - Frank Stenner
AU - Jakob Passweg
AU - Nina Khanna
AU - Lukas Jeker
AU - Mascha Binder
AU - Alfred Zippelius
AU - Heinz Läubli
PY - 2026
DA - 2026/09/15
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103051
UR - https://doi.org/10.1016/j.xcrm.2026.103051
AB - Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) induces durable responses in metastatic melanoma, yet the clonal and transcriptional dynamics governing tumor-reactive T cell fate during ex vivo expansion and after transfer remain poorly understood. Here, we perform longitudinal single-cell RNA and T cell receptor sequencing across five time points, from baseline tumors through two-phase ex vivo expansion to post-infusion blood and tumor biopsies, in seven melanoma patients, resolving both the CD8+ and CD4+ compartments. Tumor-reactive CD8+ T cells are reinvigorated from exhaustion and acquire HLA-II-high or KLF2-high profiles. We further dissect the tumor-responsive CD4+ compartment in depth, revealing lineage-dependent reinvigoration in which follicular helper T cells adopt an effector state while exhausted CD4+ T cells retain dysfunction. In non-responders, across three cohorts, co-transferred type 17 T cells and de novo regulatory T cell expansion after transfer associate with treatment failure. These data define subtype-specific signatures across both lineages to guide TIL expansion.
SN - 2666-3791
ER -