Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population 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; Meghana S Pagadala; Vishal R Dhere; Sarwish Rafiq; Aparna H Kesarwala; Alexandre Orthwein; Susan N Thomas; Mohammad K Khan; J Brandon Dixon; Gregory B Lesinski; Michael C Lowe; Haydn Kissick; David S Yu; Chrystal M Paulos; Nicole C Schmitt; Zachary S Buchwald

doi:10.21203/rs.3.rs-3921977/v1

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node

Res Sq [Preprint]. 2024 Mar 6:rs.3.rs-3921977. doi: 10.21203/rs.3.rs-3921977/v1.

Authors

Yang Shen^{1

2}, Erin Connolly^{3

2}, Meili Aiello¹, Chengjing Zhou¹, Prasanthi Chappa¹, Haorui Song¹, Patan Tippitak¹, Tarralyn Clark¹, Maria Cardenas⁴, Nataliya Prokhnevska⁵, Annapaola Mariniello^{6

7}, Meghana S Pagadala⁸, Vishal R Dhere¹, Sarwish Rafiq⁹, Aparna H Kesarwala¹, Alexandre Orthwein¹, Susan N Thomas^{10

11

12}, Mohammad K Khan¹, J Brandon Dixon^{10

11

12}, Gregory B Lesinski⁹, Michael C Lowe¹³, Haydn Kissick⁴, David S Yu¹, Chrystal M Paulos¹³, Nicole C Schmitt¹⁴, Zachary S Buchwald^{1

15}

Affiliations

¹ Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA.
² These authors contributed equally.
³ Bioinformatics Graduate Program, Georgia Institute of Technology, Atlanta, GA, USA.
⁴ Department of Urology and Winship Cancer Institute, Emory University, Atlanta, GA, USA.
⁵ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai (ICMMS), New York City, NY, USA.
⁶ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
⁷ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
⁸ Medical Scientist Training Program, University of California San Diego, La Jolla, CA USA.
⁹ Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA.
¹⁰ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
¹¹ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
¹² Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
¹³ Department of Surgery and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
¹⁴ Department of Otolaryngology - Head and Neck Surgery and Winship Cancer Institute, Emory University, Atlanta, GA, USA.
¹⁵ Lead contact.

Abstract

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

Keywords: PD-1; PD-L1; Radiation; Tcf-1; abscopal effect; checkpoint blockade; immunotherapy; stem-like T cells; tumor-draining lymph node.

Publication types

Preprint

Grants and funding

K08 CA270401/CA/NCI NIH HHS/United States