Combination radiation and αPD-L1 enhance tumor control by stimulating CD8+ PD-1+ TCF-1+ T cells in the tumor-draining lymph node
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.
Authors
- Shirley Zhang (ORCID: https://orcid.org/0000-0002-6672-2044)
- Erin C. Connolly
- Zachary S. Buchwald (ORCID: https://orcid.org/0000-0003-4407-7264)
- Alexandre Orthwein (ORCID: https://orcid.org/0000-0002-7350-3413)
- Maria A. Cardenas (ORCID: https://orcid.org/0000-0002-8566-9576)
- Gregory B. Lesinski (ORCID: https://orcid.org/0000-0002-8787-7678)
- Meghana S. Pagadala (ORCID: https://orcid.org/0000-0002-7591-6035)
- Vishal R. Dhere (ORCID: https://orcid.org/0000-0002-8364-7488)
- Michael Lowe (ORCID: https://orcid.org/0000-0003-4853-7352)
- Chrystal Mary Paulos (ORCID: https://orcid.org/0000-0002-0784-2601)
- Susan N. Thomas (ORCID: https://orcid.org/0000-0003-4651-232X)
- J. Brandon Dixon (ORCID: https://orcid.org/0000-0003-0351-4587)
- Sarwish Rafiq (ORCID: https://orcid.org/0000-0002-9295-3065)
- Nicole C. Schmitt (ORCID: https://orcid.org/0000-0002-0571-3531)
- Chengjing Zhou (ORCID: https://orcid.org/0009-0001-1518-7053)
- Haydn Kissick (ORCID: https://orcid.org/0000-0001-7624-5598)
- Nataliya Prokhnevska (ORCID: https://orcid.org/0000-0001-8588-7410)
- David S. Yu (ORCID: https://orcid.org/0000-0002-2781-5379)
- Yang Shen (ORCID: https://orcid.org/0000-0002-2448-8405)
- Aparna H. Kesarwala (ORCID: https://orcid.org/0000-0001-8297-9643)
- Prasanthi Chappa
- Isabelle De Bruyker (ORCID: https://orcid.org/0009-0004-0540-495X)
- Mohammad K. Khan (ORCID: https://orcid.org/0000-0001-7344-8592)
- Haorui Song (ORCID: https://orcid.org/0009-0005-6940-9298)
- Meili Aiello
- Annapaola Mariniello
- Patan Tippitak (ORCID: https://orcid.org/0009-0007-0626-4313)
- Tarralyn Clark
Institutions
- University of Geneva (CH)
- Georgia Institute of Technology (US)
- Emory University (US)
- The Wallace H. Coulter Department of Biomedical Engineering (US)
- University of California San Diego (US)
- Piedmont Cancer Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1038/s41467-025-58510-1
- Citations
- 10
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 10.45
Funders
- Emory University
- National Cancer Institute