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<p>Primary mediastinal large B-cell lymphoma (PMBCL) is characterized by recurrent 9p24.1 alterations driving constitutive overexpression of PD-1 ligands and high sensitivity to PD-1 blockade. While PD-L1 is widely used as a biomarker, the tumor-intrinsic functions of PD-1 ligands, and particularly PD-L2, remain poorly defined. Here, we investigated the distinct roles of PD-L1 and PD-L2 in PMBCL using CRISPR-Cas9-engineered isogenic models, immune co-culture assays, an immune-interactive <i>in ovo</i> chorioallantoic membrane (CAM) xenograft system, and integrative transcriptomic analyses of patient datasets. PD-L1 was most strongly associated with restraint of Th1-associated immune signaling and influenced responsiveness to PD-1 blockade, whereas PD-L2 was associated with preservation of lineage-associated transcriptional programs and distinct treatment-response patterns. Combined disruption of both ligands enhanced Th1 immune activation while altering B-cell transcriptional states. Consistent with these findings, transcriptomic analyses in PMBCL cohorts linked <i>PDCD1LG2</i> expression to B-cell identity and signaling modules, whereas <i>CD274</i> expression aligned with interferon-responsive immune programs. Together, these results support a model in which PD-L1 and PD-L2 associate with distinct immune and lineage-associated states in PMBCL and provide a framework for exploring biologically informed stratification strategies in this disease.</p>

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PD-L2 is associated with lineage-related transcriptional programs distinct from PD-L1 in primary mediastinal large B-cell lymphoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月1日

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  • Mélody Caillot,
  • Audrey Da Rocha,
  • Morgane Lafenêtre,
  • Marie-Delphine Lanic,
  • Pierre-Julien Viailly,
  • Elena Liana Veresezan,
  • Dominique Penther,
  • Marick Laé,
  • Fabrice Jardin,
  • Vincent Camus

摘要

Primary mediastinal large B-cell lymphoma (PMBCL) is characterized by recurrent 9p24.1 alterations driving constitutive overexpression of PD-1 ligands and high sensitivity to PD-1 blockade. While PD-L1 is widely used as a biomarker, the tumor-intrinsic functions of PD-1 ligands, and particularly PD-L2, remain poorly defined. Here, we investigated the distinct roles of PD-L1 and PD-L2 in PMBCL using CRISPR-Cas9-engineered isogenic models, immune co-culture assays, an immune-interactive in ovo chorioallantoic membrane (CAM) xenograft system, and integrative transcriptomic analyses of patient datasets. PD-L1 was most strongly associated with restraint of Th1-associated immune signaling and influenced responsiveness to PD-1 blockade, whereas PD-L2 was associated with preservation of lineage-associated transcriptional programs and distinct treatment-response patterns. Combined disruption of both ligands enhanced Th1 immune activation while altering B-cell transcriptional states. Consistent with these findings, transcriptomic analyses in PMBCL cohorts linked PDCD1LG2 expression to B-cell identity and signaling modules, whereas CD274 expression aligned with interferon-responsive immune programs. Together, these results support a model in which PD-L1 and PD-L2 associate with distinct immune and lineage-associated states in PMBCL and provide a framework for exploring biologically informed stratification strategies in this disease.