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 C. Connolly, Meili Aiello, Chengjing Zhou, Prasanthi Chappa, Haorui Song, Patan Tippitak, Tarralyn Clark, Maria A. 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 Zhang, Mohammad K. Khan, J. Brandon Dixon, Gregory B. Lesinski, Michael Lowe, Haydn Kissick, David S. Yu, Chrystal M. Paulos, Nicole C. Schmitt, Zachary S. Buchwald
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.