Assessment of tertiary lymphoid structures via (18)F-FDG PET/CT scan in patients with pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is one of the most malignancies with a poor prognosis. The immune phenotype of pancreatic cancer is remarkably complex, presenting a significant challenge to the efficacy of immunotherapy. Tertiary lymphoid structures (TLSs) are active zones composed of various immune cells, which reflect immune responses against cancer. TLSs have emerged as critical biomarkers for predicting immunotherapy outcomes, potentially reflecting alterations in the metabolic characteristics of the host. Accumulating evidence indicates that (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) may shed light on cancer immunology. The tumor environment is known to be associated with the metabolic activity and antitumor immunity of immune cells. A total of 266 patients with PAAD who underwent (18)F-FDG PET/CT followed by pancreatectomy were enrolled in this study, and the presence of TLSs was identified in 66 patients by HE staining, and fluorescent multiplex immunohistochemistry (mIHC) was employed to analyze the cellular composition of TLSs. Elevated maximum standard uptake values (SUVmax) showed significant correlation with TLS presence in PAAD patients. However, SUVmax value showed no correlation with overall survival in PAAD patients. Immunohistochemistry (IHC) staining demonstrated a statistically significant correlation between higher SUVmax levels and increased CD4 + and CD8 + tumor-infiltrating lymphocytes. In PAAD patients with TLS, CD4⁺ T-cell infiltration levels showed a positive correlation with SUVmax. In our study, a TLS signature containing 12-chemokine was proposed to determine high TLS score and low TLS score group. The high TLS score group exhibited increased infiltration of naïve/memory/activated B cells, central memory/activated CD4⁺/CD8⁺ T cells, Tregs, Th1/Th2/Th17 subsets, and neutrophils. Furthermore, GLUT3 and GLUT10 expression consistently correlated with TLS scores in both TCGA and CPTAC cohorts. GLUT3 and GLUT10 were found to be upregulated in the high TLS score group. A more inflamed immune infiltrative landscape was characterized in the high TLS score group with a high proportion of multiple immune cells. Increased FDG uptake is often induced by overexpression of glucose transporters (GLUT) and glucometabolic genes. Overexpression of GLUT3 and GLUT10 was found to be positively correlated with higher infiltration levels as well as immune activation of CD4(+) and CD8(+) T cells. To conclude, our study showed an association between SUVmax on (18)F-FDG PET/CT and TLS presence in PAAD. FDG uptake may reflect local immune responses and glucose metabolism associated with TLS presence in PAAD. (18)F-FDG PET/CT may serve as a non-invasive and aided tool for assessing the presence of TLS in tumor immune environment and predicting antitumor immunity in PAAD patients.