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

Yang Shen, Erin Connolly, Meili Aiello, Chengjing Zhou, Prasanthi Chappa, Haorui Song, Patan Tippitak, Tarralyn Clark, Maria Cardenas, Nataliya Prokhnevska, Annapaola Mariniello, Isabelle 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 and Zachary S. Buchwald ()
Additional contact information
Yang Shen: Emory University
Erin Connolly: Georgia Institute of Technology
Meili Aiello: Emory University
Chengjing Zhou: Emory University
Prasanthi Chappa: Emory University
Haorui Song: Emory University
Patan Tippitak: Emory University
Tarralyn Clark: Emory University
Maria Cardenas: Emory University
Nataliya Prokhnevska: Icahn School of Medicine at Mount Sinai (ICMMS)
Annapaola Mariniello: University of Geneva
Isabelle Bruyker: Georgia Institute of Technology and Emory University
Meghana S. Pagadala: University of California San Diego
Vishal R. Dhere: Emory University
Sarwish Rafiq: Emory University
Aparna H. Kesarwala: Emory University
Alexandre Orthwein: Emory University
Susan N. Thomas: Georgia Institute of Technology and Emory University
Shirley L. Zhang: Emory University School of Medicine
Mohammad K. Khan: Emory University
J. Brandon Dixon: Georgia Institute of Technology and Emory University
Gregory B. Lesinski: Emory University
Michael C. Lowe: Department of Surgery and Winship Cancer Institute of Emory University
Haydn Kissick: Emory University
David S. Yu: Emory University
Chrystal M. Paulos: Department of Surgery and Winship Cancer Institute of Emory University
Nicole C. Schmitt: Emory University
Zachary S. Buchwald: Emory University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58510-1

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