️ Episode 210: Tumour-Reactive CD8 T Cell Clusters in Human Melanoma
In this episode of PaperCast Base by Base, we explore how tumour-reactive CD8 T cells organize into stable clusters with melanoma cells and antigen-presenting cells, and how these structures can be isolated from patient samples to boost anti-tumour immunity.

Study Highlights:
The authors used conventional and imaging flow cytometry to identify heterotypic clusters in which CD8 T cells were physically conjugated to tumour cells and antigen-presenting cells across 21 human melanoma metastases. Single-cell RNA and TCR sequencing showed that clustered CD8 T cells were more clonally expanded and displayed gene expression signatures of tumour reactivity, activation and exhaustion, whereas single CD8 T cells were enriched for naive and bystander-like states. Specific melanoma and myeloid subpopulations with strong antigen-presentation, interferon signalling and chemokine expression were preferentially engaged in these clusters, highlighting non-random, ligand–receptor-driven interactions in the tumour microenvironment. When expanded ex vivo, T cells derived from clusters produced more cytokines and showed markedly higher cytotoxicity against autologous melanoma cells than T cells from singlets. In mouse models bearing patient-derived melanomas, adoptive transfer of cluster-derived T cells led to stronger T cell infiltration, activation and tumour control than transfer of T cells expanded from single-cell gates.

Conclusion:
Heterotypic CD8 T cell clusters represent a powerful and previously overlooked source of tumour-reactive T cells and TCRs that could be harnessed to refine and enhance adoptive T cell therapies, including TIL-based treatment strategies.

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Ibáñez-Molero S, Veldman J, Nieto JS, Traets JJH, George A, Hoefakker K, Karomi A, Harkes R, van den Broek B, Pack SM, Tas L, Visser NL, van Hal-van Veen SE, Alóndiga-Mérida P, Alkemade M, Seignette IM, Tissier R, Nieuwland M, van Baalen M, Poźniak J, Mul E, Tol S, Stenqvist S, Nilsson LM, Nilsson JA, Haanen JBAG, van Houdt WJ, Peeper DS. Tumour-reactive heterotypic CD8 T cell clusters from clinical samples. Nature. 2025. https://doi.org/10.1038/s41586-025-09754-w

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Chapters

• (00:00:00 ) - The Paradox of the Immune System
• (00:02:31 ) - Immunity clusters in melanoma
• (00:08:13 ) - Immunity 4, Cluster-derived T cells
• (00:11:45 ) - Cluster Analysis for T-cell protection
• (00:14:52 ) - Crowded Storms