PET/CT molecular imaging in the era of immune-checkpoint inhibitors therapy

Abstract

Cancer immunotherapy, especially immune-checkpoint inhibitors (ICIs), has paved a new way for the treatment of many types of malignancies, particularly advanced-stage cancers. Accumulating evidence suggests that as a molecular imaging modality, positron emission tomography/computed tomography (PET/CT) can play a vital role in the management of ICIs therapy by using different molecular probes and metabolic parameters. In this review, we will provide a comprehensive overview of the clinical data to support the importance of ¹⁸F-fluorodeoxyglucose PET/CT (¹⁸F-FDG PET/CT) imaging in the treatment of ICIs, including the evaluation of the tumor microenvironment, discovery of immune-related adverse events, evaluation of therapeutic efficacy, and prediction of therapeutic prognosis. We also discuss perspectives on the development direction of ¹⁸F-FDG PET/CT imaging, with a particular emphasis on possible challenges in the future. In addition, we summarize the researches on novel PET molecular probes that are expected to potentially promote the precise application of ICIs.

Keywords: immune-checkpoint inhibitors (ICIs); metabolic parameter; molecular imaging; molecular probe; positron emission tomography/computed tomography (PET/CT); tumor microenvironment (TME).

Figure 1

Tumor microenvironment (TME) is composed of tumor cells, immune cells, stromal cells, extracellular matrix, and exosomes, thus forming a microenvironment with the characteristics of inflammation, hypoxia, acidity, and immunosuppression. Different types of cells in TME have their preferred metabolic phenotypes. OXPHOS, oxidative phosphorylation; HBP, hexosamine biosynthesis pathway; PPP, pentose phosphate pathway; MDSC, myeloid-derived suppressor cell; Treg cell, regulatory T cell; M2-TAM, immunosuppressive macrophages; Tmem cell, CD8⁺ memory T cells; DC, dendritic cell; Teff cell, CD8⁺ effector T cells; NK cell, natural killer cell; M1-TAM, inflammatory tumor-associated macrophages; CAF, cancer-associated fibroblast; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; IL-2, Interleukin-2; IFN-γ, Interferon-γ; ECM, extracellular matrix.

Figure 2

The application of ¹⁸F-FDG PET/CT imaging in tumor immunotherapy includes characterization of tumor immune microenvironment (TIME), assessment of immune-related adverse events (irAEs), evaluation of therapeutic efficacy, and prediction of prognosis.

Figure 3

Typical images of irAEs in patients with ICI treatment. (A), thyroiditis; (B), hypophysitis; (C), pneumonia; (D), pancreatitis; (E), enteritis. The sites of irAEs were marked with blue arrows on maximum intensity projection (MIP) and PET images.

Figure 4

Typical cases evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with ICI treatment. (A), Immunotherapy response in a 64-year-old male patient with right lung adenocarcinoma. The baseline image shows intensive FDG uptake in the primary tumor, accompanied with multifocal intrapulmonary metastasis, lymphadenopathy, and the involvement of pleura. Follow-up images after 4 cycles and sequential 11 cycles of the combination of chemotherapy and ICI show partial response (PR). (B), Immunotherapy response in a 60-year-old female patient with right lung adenocarcinoma. Image after 7 cycles of the combination of chemotherapy and ICI shows the enlargement and increased metabolism in the primary tumor, and the onset of multiple new lesions in the lung, pleura, lymph nodes, liver, and bone, indicating progressive disease (PD).

Figure 5

A series of new PET molecular probes targeting the compositions of tumor microenvironment (TME).