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Background <p>CAR-T cell therapy has improved outcomes in relapsed/refractory large B cell lymphoma (LBCL), yet responses remain variable; baseline endogenous T cell state and post-infusion CAR-T differentiation may contribute to this heterogeneity, but the underlying transcriptional programs are incompletely defined.</p> Methods <p>We performed RNA-sequencing of CD3⁺ T cells from 26 LBCL patients at two time points—pre-apheresis (PA; <i>n</i> = 23) and day 14 post-infusion (D14; <i>n</i> = 9)—and applied differential expression, gene set enrichment analysis (GSEA), and gene regulatory network inference.</p> Results/Interpretation <p>In PA T cells, we identified 320 differentially expressed genes enriched for immune-related programs (TCR signaling, T cell differentiation, IL-2–related signaling, TCR regulation of apoptosis and misregulation of cancer) and signatures consistent with immune dysfunction. Unsupervised clustering defined two LBCL T cell expression profiles, which were strongly associated with early disease progression (91% vs 16%; <i>P</i> &lt; 0.001), supporting a hyperactivated yet progressively dysfunctional T cell state that may compromise CAR-T fitness and persistence. At the pathway level, GSEA in LBCL PA T cells showed enrichment of PI3K/AKT/mTOR and <i>MYC</i> target programs together with apoptosis-related signatures.</p> Conclusions <p>Transcriptomic heterogeneity in endogenous T cells is strongly linked to early post-CAR-T progression and may inform strategies to optimize CAR-T persistence and efficacy.</p>

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Transcriptomic landscape of peripheral T cells following CAR-T cell therapy in diffuse large B cell lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Ismael de la Iglesia-San Sebastián,
  • Sara Fernández de Córdoba-Oñate,
  • Mariana Bastos-Oreiro,
  • Raquel Fernández-González,
  • Miguel López-Esteban,
  • Rebeca Bailén,
  • Ignacio Gómez-Centurión,
  • Dolores Fuentes,
  • Javier Anguita,
  • Mi Kwon,
  • Ramón García-Sanz,
  • Ismael Buño,
  • Carolina Martínez-Laperche

摘要

Background

CAR-T cell therapy has improved outcomes in relapsed/refractory large B cell lymphoma (LBCL), yet responses remain variable; baseline endogenous T cell state and post-infusion CAR-T differentiation may contribute to this heterogeneity, but the underlying transcriptional programs are incompletely defined.

Methods

We performed RNA-sequencing of CD3⁺ T cells from 26 LBCL patients at two time points—pre-apheresis (PA; n = 23) and day 14 post-infusion (D14; n = 9)—and applied differential expression, gene set enrichment analysis (GSEA), and gene regulatory network inference.

Results/Interpretation

In PA T cells, we identified 320 differentially expressed genes enriched for immune-related programs (TCR signaling, T cell differentiation, IL-2–related signaling, TCR regulation of apoptosis and misregulation of cancer) and signatures consistent with immune dysfunction. Unsupervised clustering defined two LBCL T cell expression profiles, which were strongly associated with early disease progression (91% vs 16%; P < 0.001), supporting a hyperactivated yet progressively dysfunctional T cell state that may compromise CAR-T fitness and persistence. At the pathway level, GSEA in LBCL PA T cells showed enrichment of PI3K/AKT/mTOR and MYC target programs together with apoptosis-related signatures.

Conclusions

Transcriptomic heterogeneity in endogenous T cells is strongly linked to early post-CAR-T progression and may inform strategies to optimize CAR-T persistence and efficacy.