Journal Article

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

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

2025

Overview

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. Combination radiotherapy (RT) + αPD-L1 enhances tumor control via a tumor-draining lymph node (TdLN)-derived CD8+ PD-1+ TCF-1+ T cells. RT + αPD-L1 induces a novel LY6A+ subset in the TdLN that migrates to the tumor and differentiates into effectors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 38/91 / 631/250/580 / 631/67/1059 / 631/67/580 / 64/60 / Ablation / Animal models / Animals / Antigens, Ly / B7-H1 Antigen - immunology / B7-H1 Antigen - metabolism / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - radiation effects / Cell differentiation / Cell Line, Tumor / Combined Modality Therapy / Effector cells / Female / Hepatitis A Virus Cellular Receptor 2 - metabolism / Hepatocyte nuclear factor 1 / Hepatocyte Nuclear Factor 1-alpha - metabolism / Humanities and Social Sciences / Lymph nodes / Lymph Nodes - drug effects / Lymph Nodes - immunology / Lymph Nodes - pathology / Lymph Nodes - radiation effects / Lymphatic system / Lymphocytes / Lymphocytes T / Melanoma / Melanoma, Experimental - immunology / Melanoma, Experimental - pathology / Melanoma, Experimental - radiotherapy / Melanoma, Experimental - therapy / Membrane Proteins / Mice / Mice, Inbred C57BL / multidisciplinary / PD-1 protein / Programmed Cell Death 1 Receptor - immunology / Programmed Cell Death 1 Receptor - metabolism / Radiation therapy / Science / Science (multidisciplinary) / T Cell Transcription Factor 1 - metabolism / Tumors