The Warburg effect is a hallmark of tumors[12]. Tumor glycolysis is regulated by various oncogenes, cancer suppressor genes, and the tumor microenvironment, so tumor glycolysis is closely related to the biological properties of tumors[13–15]. Some studies have reported that the 18F-FDG uptake in HCC correlates with tumor microvascular invasion (MVI), and SUVmax > 5.85 is the best cut-off value to differentiate MVI-positive HCC in 18F-FDG PET/CT imaging[16]. Yoh et al. demonstrated that the FDG uptake capacity of HCC was strongly correlated with survival prognosis of patients[17]. In the present study, we first evaluated the correlation between FDG uptake, based on the SUVmax value, and the pathological characteristics of patients with HCC. Our results showed that the SUVmax value was significantly correlated with the degree of differentiation, tumor size, portal vein embolism formation, lymph node metastasis, distant organ metastasis, and patient survival status in HCC (P < 0.05), consistent with the findings of many current studies.
Tumor immune escape and immunotherapy sensitivity are current research hotspots in oncology research. Tumor immune escape and immunotherapy efficacy are closely related to PD-L1 expression in tumor cells and inflammatory cell infiltration in the tumor microenvironment[18, 19]. Therefore, in this study, we further compared the relationship between SUVmax and PD-L1 expression as well as inflammatory cell infiltration in HCC to explore the relationship between tumor immunity through HCC FDG uptake and tumor immunity. Cytotoxic T cells, regulator T cells, and M2 macrophages are important cells that regulate tumor immunity in the tumor microenvironment, and these inflammatory cells can take up glucose themselves, thereby increasing the tumor FDG uptake value and the SUVmax[20]. Shinji Itoh et al. found that FDG uptake in HCC was positively correlated with CD8 + T-cell counts and CD68 + macrophage infiltration in HCC[21]. Young-Sil An demonstrated that FDG uptake in breast cancer brain metastases is correlated with macrophage infiltration[22]. Our study showed that many HCC tissues show infiltration of cytotoxic T cells and M2 macrophage cells, and the number of infiltrating cells was positively correlated with FDG uptake, but the number of regulatory T cells infiltrating HCC tissues was relatively small and did not correlate with FDG uptake. Thus, 18F-FDG PET/CT may be useful to evaluate the status of inflammatory cell, especially cytotoxic T-cell and M2 macrophage, infiltration in HCC.
PD-L1 is an important immune checkpoint and immunotherapy target, and prediction of PD-L1 expression can help guide immunotherapy. Several studies have explored the prediction of tumor PD-L1 expression status on the basis FDG uptake. Ruohua Chen et al.[23] showed that high 18F-FDG uptake by bladder cancer is associated with elevated PD-1/PD-L1 expression and that SUVmax = 22.7 was the best cut-off value to predict high PD-L1 expression in bladder cancer. In this study, our results also showed that the SUVmax in HCC was closely correlated with PD-L1 expression. HCC with high PD-L1 expression was usually accompanied by higher SUVmax values, suggesting that high PD-L1 expression was a malignant feature of high glucose metabolism in HCC. It may be useful to assess PD-L1 expression in HCC patients by 18F-FDG PET/CT, and thereby guide clinical immunotherapy. However, the mechanism underlying the association between FDG uptake and PD-L1 protein expression has not been fully elucidated. One possible mechanism is that lactate-induced TAZ-dependent upregulation of PD-L1 expression in tumor tissues [24], in addition to the key genes regulating glucose metabolism, PKM2, and hypoxia factor, regulates PD-L1 expression[25, 26].
The tumor PD-L1 expression status is closely related to the efficacy of immunotherapy. In order to better predict PD-L1 expression, we further analyzed the correlation between PD-L1 expression and different clinical characteristics and found that PD-L1 expression was also significantly correlated with tumor differentiation, size, portal vein tumor thrombosis, and patient survival status. Multifactorial analysis further confirmed that SUVmax, the number of infiltrating M2 cells, and portal vein tumor thrombosis were independent predictors of PD-L1 expression. In fact, several studies have demonstrated that M2 macrophages are associated with PD-L1 expression, and the mechanism may be related to the direct induction of PD-L1 expression by M2 macrophages secreting transforming growth factor (TGF)-β1 in tumor cells[27]. The molecular mechanisms underlying the correlation between portal vein tumor thrombosis and PD-L1 expression are unclear. We speculate that HCC with high PD-L1 expression may secrete more Cytokines[28, 29], such as interleukins leading to targeted migration of HCC cells to the portal vein [30, 31]. Nevertheless, the specific molecular mechanisms need to be further explored.
Although SUVmax, the number of infiltrating M2 cells, and portal vein thrombosis were closely correlated with PD-L1 expression in HCC, direct assessment of the number of infiltrating inflammatory cells with PET/CT or currently available imaging tools is difficult. Therefore, we selected two parameters, SUVmax and the presence of portal vein tumor thrombosis, and attempted to predict PD-L1 expression on the basis of 18F-FDG PET/CT images alone. In the ROC analysis, the highest sensitivity and specificity for predicting PD-L1 was observed when the SUVmax cut-off value for HCC was 4.55. When the SUVmax and portal vein tumor thrombus were combined to predict PD-L1 expression, the area under the ROC line was larger than that obtained with SUVmax alone, indicating that the combination of SUVmax and portal vein tumor thrombus could better predict PD-L1 expression in HCC than a single index. On the basis of our findings, patients with HCC could be divided into a high-probability group, medium-probability group, and low-probability group for PD-L1 expression. Our results showed that the probability of high PD-L1 expression in the high-probability group was 87.5%, while the probability of high PD-L1 expression in the low-probability group was only 12.7%. These results further suggest that the combined assessment of SUVmax values and the presence of portal vein tumor thrombosis by 18F-FDG PET/CT imaging can help determine PD-L1 expression in HCC. Nevertheless, the study had some limitations. Due to the limited number of patients, some validation cohorts are missing, necessitating a prospective validation study to confirm the current findings.