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<p>Combination radiotherapy (RT) and αPD-L1 therapy has potential to enhance local and distant (abscopal) tumor control, however, clinical results in humans have been variable. Using murine melanoma models, we found RT + αPD-L1 increases intra-tumor progenitor CD8+ PD-1+ TCF-1+ T cells. This increase depends on trafficking of the PD-1+ TCF-1+ cells from the tumor-draining lymph node (TdLN) to the tumor. RT alone promotes the expansion and differentiation of the TdLN derived PD-1+ TCF-1+ cells into TIM-3+ GZMB+ TCF-1- effector-like cells in the tumor with further enhancement after the addition of αPD-L1. In the TdLN, combination therapy enriches for a novel PD-1+ TCF-1+ TOX- LY6A+ subset with expression of a type I interferon and migratory signature. This subset is able to traffic to the tumor and differentiate into TIM-3+ TCF-1- cells. Finally, we found that ablation of the PD-1+ TCF-1+ T cell population attenuates the enhanced tumor control observed with combination RT + αPD-L1. These results suggest that abscopal response failures may be secondary to impaired stimulation of TdLN CD8+ PD-1 + TCF-1+ T cells or an inability of PD-1+ TCF-1+ cells in the TdLN to traffic to the tumor.</p>

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Combination radiation and αPD-L1 enhance tumor control by stimulating CD8+ PD-1+ TCF-1+ T cells in the tumor-draining lymph node

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月14日

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  • Yang Shen,
  • Erin Connolly,
  • Meili Aiello,
  • Chengjing Zhou,
  • Prasanthi Chappa,
  • Haorui Song,
  • Patan Tippitak,
  • Tarralyn Clark,
  • Maria Cardenas,
  • Nataliya Prokhnevska,
  • Annapaola Mariniello,
  • Isabelle De Bruyker,
  • Meghana S. Pagadala,
  • Vishal R. Dhere,
  • Sarwish Rafiq,
  • Aparna H. Kesarwala,
  • Alexandre Orthwein,
  • Susan N. Thomas,
  • Shirley L. Zhang,
  • Mohammad K. Khan,
  • J. Brandon Dixon,
  • Gregory B. Lesinski,
  • Michael C. Lowe,
  • Haydn Kissick,
  • David S. Yu,
  • Chrystal M. Paulos,
  • Nicole C. Schmitt,
  • Zachary S. Buchwald

摘要

Combination radiotherapy (RT) and αPD-L1 therapy has potential to enhance local and distant (abscopal) tumor control, however, clinical results in humans have been variable. Using murine melanoma models, we found RT + αPD-L1 increases intra-tumor progenitor CD8+ PD-1+ TCF-1+ T cells. This increase depends on trafficking of the PD-1+ TCF-1+ cells from the tumor-draining lymph node (TdLN) to the tumor. RT alone promotes the expansion and differentiation of the TdLN derived PD-1+ TCF-1+ cells into TIM-3+ GZMB+ TCF-1- effector-like cells in the tumor with further enhancement after the addition of αPD-L1. In the TdLN, combination therapy enriches for a novel PD-1+ TCF-1+ TOX- LY6A+ subset with expression of a type I interferon and migratory signature. This subset is able to traffic to the tumor and differentiate into TIM-3+ TCF-1- cells. Finally, we found that ablation of the PD-1+ TCF-1+ T cell population attenuates the enhanced tumor control observed with combination RT + αPD-L1. These results suggest that abscopal response failures may be secondary to impaired stimulation of TdLN CD8+ PD-1 + TCF-1+ T cells or an inability of PD-1+ TCF-1+ cells in the TdLN to traffic to the tumor.