PET imaging of endogenous markers of T-cell response

Introduction: Our purpose is to provide an overview of the applications of state-of-the-art T-cell positron emission tomography (PET) imaging and the potential it has to improve the clinical management of patients receiving cancer immunotherapy. T-lymphocytes are by far the most abundant lymphocyte type acting as the key mediators of the adaptive immune response. T-cells, once activated, expand and create potent effector mechanisms for eliminating aberrant cells. Imbalanced or inappropriate T-cell responses underlie cancer progression. These cell types have been a primary focus in the molecular imaging field owing to the growth in T-cell-based therapeutics and due to T-cells’ dominant roles in cancer immunopathology and driving anti-cancer responses. The noninvasive PET imaging approach has the potential to provide comprehensive information about the distribution and abundance of immune cell subsets in vivo. With these imaging strategies capable of visualizing T-cell dynamics in real-time, clinicians can be better informed about the adaptive immune response and T-cell behaviors in different settings, which would greatly enhance our understanding of their role in disease pathogenesis and facilitate personalized medicine.

Methods: PubMed was queried for trials pertaining to the endogenous PET imaging biomarkers, specifically associated with T lymphocytes.

Results: Immunotherapy is a rapidly expanding and evolving approach to treating cancer. Biopsy and peripheral blood analyses are currently recognized as the gold standards to assess immune responses following immunotherapy, which do not reflect the dynamic spatiotemporal aspects of immune responses. Efforts are underway to develop comprehensive ex vivo evaluations of the immune landscape of patients prior to and during response to immunotherapy. In order to visualize the T-cell response in the context of immunotherapy, PET imaging offers desired characteristics such as easy quantification, high sensitivity, and availability. This noninvasive imaging method using appropriate probes represents an ideal whole-body modality to monitor the spatiotemporal dynamics of T-cells and their functional status and has shown high potential to become an integral tool for further developing cancer immunotherapy, assessing delivery of immune-based therapeutics, and evaluating responses to immunotherapy. Characterization and targeting of endogenous biomarkers specific to T-lymphocytes enable their noninvasive visualization in their native environment without the need for ex vivo genetic or radiochemical manipulation, thereby demonstrating their distinct behaviors comprising activation, proliferation, trafficking, inhibition, and cytotoxic effector functions. This has motivated the development and evaluation of a wide range of T-cell imaging probes in both preclinical studies and clinical trials. Endogenous T-cell biomarkers include cell surface lineage markers (such as cluster of differentiation (CD)3, CD4, and CD8), cell surface activation markers (such as CD25, CD69, CD134, and CD278), secreted markers of CD8+ T-cell cytotoxicity (such as granzyme B and interferon-gamma), cell surface markers for inhibition and control (such as CD152 and CD279), and intracellular metabolic enzymes (such as deoxycytidine kinase, deoxyguanosine kinase, hexokinases, and thymidine kinase 1). Notwithstanding the great potential of the T-cell PET imaging approaches for improving clinical management of cancer immunotherapy and diagnosis of T-cell driven immunopathology, further optimization of these strategies is still warranted to overcome limitations in their safety and specificity.

Conclusions: This educational exhibit will elaborate on the candidate targets for visualization of endogenous markers of T-cell responses at various stages along the cancer-immunity cycle in the context of immunotherapy. We also discuss the applications, merits and limitations of T-cell PET imaging and the potential use of this imaging toolbox in patients treated with cancer immunotherapy.