Visualizing T-Cell Responses: The T-Cell PET Imaging Toolbox

Abstract

T lymphocytes are key mediators of the adaptive immune response. Inappropriate or imbalanced T-cell responses are underlying factors in cancer progression, allergy, and other immune disorders. Monitoring the spatiotemporal dynamics of T cells and their functional status has the potential to provide unique biologic insights into health and disease. Noninvasive PET imaging represents an ideal whole-body modality for achieving this goal. With the appropriate PET imaging probes, T-cell dynamics can be monitored in vivo with high specificity and sensitivity. Herein, we provide a comprehensive overview of the applications of this state-of-the-art T-cell PET imaging toolbox and the potential it has to improve the clinical management of cancer immunotherapy and T-cell-driven diseases. We also discuss future directions and prospects for clinical translation.

Keywords: T-cell PET imaging; cancer immunotherapy; graft-versus-host disease; inflammatory bowel disease; rheumatoid arthritis.

Graphical abstract

FIGURE 1.

Approaches to PET imaging of T cells. T-cell PET imaging toolbox expanded rapidly over last decade. (A) Numerous T-cell–specific PET tracers have been developed, including radiolabeled antibodies and antibody fragments, protein scaffolds, small molecules, and tracers complementary to reporter genes that can be used to track engineered T cells. (B) These approaches have been evaluated in both preclinical and clinical studies. (C) Noninvasive PET imaging of T cells has potential to be highly useful, allowing preclinical researchers and clinicians to predict or monitor therapeutic response to cancer immunotherapy. This modality also enables early diagnosis of inflammatory diseases, such as GVHD, RA, and inflammatory bowel disease, for timely and effective intervention.

FIGURE 2.

PET imaging of T cells for early detection of inflammatory diseases. (A) ¹⁸F-AraG enables detection of T-cell activation in cervical lymph nodes during acute GVHD (7). (B) OX40 immuno-PET allows early diagnosis of acute GVHD, before overt clinical symptoms (9). (C) ¹⁸F-AraG imaging detects RA in mouse model of adjuvant-induced arthritis (11). (D) ⁸⁹Zr-labeled CD4-targeting cys-diabody allows detection of inflammatory bowel disease (white arrow indicating mesenteric lymph nodes) (13). CLN = cervical lymph nodes; I = intestine; M = mesenteric lymph node, S = spleen.

FIGURE 3.

PET imaging of T cells enables monitoring of treatment response in cancer immunotherapy. (A) ICOS immuno-PET with ⁸⁹Zr-DFO-ICOS monoclonal antibody visualizes and predicts therapeutic response in mouse model of Lewis lung cancer treated intratumorally with STING agonist and PD-1 blockade (37). (B) OX40 immuno-PET imaging enables visualization of activated T cells in A20 tumor–bearing mouse treated intratumorally with CpG (arrow represents CpG-treated tumor) (44). (C) Elevated uptake of 2-chloro-2′-deoxy-2′-¹⁸F-fluoro-9-b-d-arabinofuranosyl-adenine was observed in several lymph nodes (arrows) of recurrent glioblastoma patient after treatment with tumor lysate–pulsed DCVax and PD-1 blockade (bottom), compared with before treatment (top) (29). (D) ¹⁸F-FHBG enables visualization of HSV-TK1 reporter gene–modified interleukin-13 CAR-T cells (arrows) in recurrent glioblastoma patients (top, before CAR-T infusion; bottom, after CAR-T infusion) (32). T = treated tumor.