Shen et al. studied abscopal effects of radiation therapy (RT) in murine melanoma and showed that RT, with or without anti-PD-L1 treatment, induced TdLN-derived PD-1+TCF-1+CD8+ T cells to infiltrate tumors. scRNAseq analyses showed that in tdLNs, RT+anti-PD-L1 therapy expanded a novel progenitor Tcf7+Klrk1+Ly6a+CD8+ T cell subset expressing a migratory and IFN-I gene profile. Their migration, expansion and differentiation into TCF-1-TIM-3+ GZMB+CD8+ TEFF-like cells was induced by RT alone, and was further promoted by anti-PD-L1. The use of knock-in mice to ablate TCF-1+ T cells confirmed the role of PD-1+ TCF-1+CD8+ T cells in RT+anti-PD-L1-induced tumor control.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (2) Bioinformatics Graduate Program, Georgia Institute of Technology, Atlanta
Author Info: (1) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (2) Bioinformatics Graduate Program, Georgia Institute of Technology, Atlanta, GA, USA. (3) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (4) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (5) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (6) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (7) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (8) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (9) Department of Urology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (10) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai (ICMMS), New York City, NY, USA. (11) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (12) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. (13) Medical Scientist Training Program, University of California San Diego, La Jolla, CA, USA. (14) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (15) Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (16) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (17) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (18) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. (19) Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA. (20) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (21) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. (22) Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (23) Department of Surgery and Winship Cancer Institute of Emory University, Atlanta, GA, USA. (24) Department of Urology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (25) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (26) Department of Surgery and Winship Cancer Institute of Emory University, Atlanta, GA, USA. (27) Department of Otolaryngology - Head and Neck Surgery and Winship Cancer Institute, Emory University, Atlanta, GA, USA. (28) Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA. zbuchwa@emory.edu.
