Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival following Immunotherapy in Murine GBM.
Michal Nisnboym Ziv1, Sarah R. Vincze3, Itay Raphael4, Zujian Xiong4, Chaim T. Sneiderman4, Rebecca A. Raphael2, Bo Li4, Ambika P. Jaswal4, ReidAnn Sever4, Kathryn E. Day2, Joseph D. LaToche2, Lesley M. Foley2, T. Kevin Hitchens2, Sameer Agnihotri4, Baoli Hu4, Dhivyaa Rajasundaram4, Carolyn J. Anderson5, Deborah T. Blumenthal6, Thomas M. Pearce7, Shikhar Uttam2, Jessie R. Nedrow2, Ashok Panigrahy4, Ian F. Pollack4, Frank S Lieberman2, Jan Drappatz8, Wilson B. Edwards5, Gary Kohanbash9
1Neuro-oncology Program, Division of Hematology/Oncology, UPMC Hillman Cancer Center, 2UPMC Hillman Cancer Center, 3Department of Neurological Surgery, UPMC Children's Hospital of Pittsburgh, 4UPMC Children's Hospital of Pittsburgh, 5University of Missouri, 6Tel-Aviv Sourasky Medical Center, Tel-Aviv University, 7University of Pittsburgh School of Medicine, 8University of Pittsburgh Cancer Institute, 9Pitt
Objective:
We aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM.
Background:
Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some GBM patients, however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cells activation.
Design/Methods:
We performed CD69 immunostaining on human and mouse T-cells following in vitro activation and post-immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequence (scRNA-seq) data from recurrent GBM patients receiving ICI. Radiolabeled CD69 antibody (Ab) positron emission tomography/computed tomography (PET/CT) imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy
Results:
CD69 expression was upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TILs) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from ICI-treated recurrent GBM patients as compared with TILs from a control cohort. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a strong positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements.
Conclusions:
Our study supports the use of CD69 immuno-PET as an early immunotherapy response assessment imaging tool for GBM patients