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Stochasticity in cancer immunotherapy stems from rare but functionally-critical Spark T cells

GSE292937 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2025/07/14 Platform GPL30172
Summary
Cancer immunotherapies trigger highly variable responses in patients and in genetically identical mice models. To assess the intrinsic stochasticity of these therapies, we performed thousands of well-controlled ex vivo immunoassays. We show that leukocyte responses and tumor cytotoxicity are highly variable at the macroscopic level and statistically distributed as a shifted Poisson process. Stochastic activation of a rare subpopulation of T cells (so-called Spark T cells) coupled to a paracrine IFN-γ- driven positive feedback account for this measured “noise” in immunotherapeutic reactions. We integrated these quantitative insights in a custom-designed machinelearning pipeline to analyze immune reactions with single-cell resolution; this led us to phenotypically and functionally identify the Spark T cells in murine naïve T cells, and in human T cell blasts, as prepared for adoptive T cell therapy. We then demonstrate their relevance in explaining variable outcomes in cancer immunotherapies.
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Also filed as BioProject PRJNA1242189 and SRA study SRP573178. Searching any of these in the dataset finder brings you back here.

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