Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy
Year: 2026
Type: article
Abstract: Adoptive cell therapy (ACT) with expanded autologous tumor-infiltrating lymphocytes (TILs) can induce durable responses in metastatic melanoma, yet many patients relapse. We profiled tumor-reactive T cell dynamics during TIL therapy using single-cell RNA and TCR sequencing from seven patients to elucidate underlying reasons. We found that tumor-reactive T cells preferentially expanded early during ex vivo TIL culture, transitioning from exhausted to reinvigorated effector states. Particularly, CD8 + exhausted T cells (Tex) and CD4 + follicular helper T cell (Tfh), but not CD4 + Tex, were efficiently reinvigorated. Further, we resolved the heterogeneity of tumor-reactive CD8 + and CD4 + subsets, defining unique signatures for their identification during TIL expansion. In addition, non-responders (NRs) exhibit increased levels of Type 17 T cells in TIL products, suggesting a potential association with resistance to therapy. After transfer, tumor-reactive clones rapidly extravasated and established a stem-like reservoir. However, in NRs, CD4 + regulatory T cells (Tregs) expanded de novo and tumor-reactive CD8 + T cells reacquired exhaustion markers, limiting their functionality. By contrast, responders (Rs) retained a pool of less differentiated, stem-like cells. Collectively, these data provide a comprehensive analysis of T cell fates during TIL-ACT providing the basis for new approaches to enhance therapeutic strategies.
Source: Cell Reports Medicine
Authors: Michael T. Sandholzer, Clara Serger, Alessia G. Liner, Sarp Uzun, David König, Helen Thut, Reto Ritschard, Jonas D. Fürst, Andreas Zingg, Natalia Rodrigues Mantuano, Benjamin Kasenda, Katharina Glatz, Elisabeth A. Kappos, Matthias Matter, Andreas Holbro, Frank Stenner, Jakob Passweg, Nina Khanna, Lukas Jeker, Mascha Binder, Alfred Zippelius, Heinz Läubli
Institutions: University of Basel, University Hospital of Basel
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Award: G9000358101
OpenAlex ID: W7213254054