br Materials and methods br Results br Discussion
Materials and methods
Discussion To the best of our knowledge, ours is the first study to examine the relationship between the immune microenvironment and 18F-FDG PET results in patients with SCLC. The low expressions of CD8 and CD4 correlated with a high 18F-FDG uptake. Our study also indicated that the SUVmax was an independent prognostic factor in patients with limited disease-SCLC but not in those with extensive disease-SCLC. The concept of “hot” and “cold” tumors, wherein tumors are immunologically classified into “hot” or “cold” phenotypes based on the demonstration of either high or low immune-cell infiltration, respectively, is a relatively new idea [22,23]. Immunologically “cold” tumors are biologically prone to possess a stem-like phenotype , and recent studies found a correlation between the SUVmax and expression of PD-L1 in NSCLC [20,21,24,25]. Lopci et al. reported a correlation between the SUVmax and CD8-TIL expression . However, other studies showed no correlations between the SUVmax and TILs in patients with NSCLC [20,21]. The results of our study demonstrated that the low expressions of CD8 and CD4 were closely correlated with high 18F-FDG uptake, although 18F-FDG uptake was not significantly associated with the expression of PD-L1 and GLUT1. Likewise, GLUT1 and Foxp3 expression levels were correlated in patients with low CD8 and CD4 levels. These data suggest that a high SUVmax might reflect a “cold” tumor microenvironment in SCLC. 18F-FDG PET might be useful in distinguishing responders from non-responders during treatment with immunocheckpoint inhibitors for SCLC. The PD-L1 positivity rates in patients with SCLC ranged between 0% and 71.6% in previous studies [, , , , ,, , , ]; in our study, this rate was 36.7% with the E1L3N RGX-104 and 41.8% with the 28-8 clone. PD-L1 is reported to be closely correlated with the expression of GLUT1 in patients with renal-cell carcinoma, Hodgkin’s lymphoma, squamous cell lung carcinoma, and lung adenocarcinoma [20,21,30,31]. A significant relationship has also been observed between PD-L1 and HIF-1α expression in patients with pulmonary pleomorphic carcinoma, oral squamous carcinoma, squamous cell lung carcinoma, and lung adenocarcinoma [20,21,32,33]. To our knowledge, our study is the first to demonstrate an association between PD-L1 and GLUT1 in patients with SCLC (p = 0.04). Additionally, a high expression of PD-L1 was correlated with worse prognosis. The role of PD-L1 expression as a prognostic marker is controversial; some previous studies demonstrated that high PD-L1-positivity is associated with better prognosis [26,29,, , , , ], while others found it to be associated with poor prognosis [27,, , , , , , , ]. This inconsistency may stem from the timing of obtaining the tumor sample, the diversity of anti-PD-L1 antibodies used, and the inconsistent cut-off values for PD-L1 expression. In our study, the PD-L1 and SUVmax were independent prognostic factors for patients with limited disease-SCLC but not in those with extensive disease-SCLC. Since previous studies have discovered a correlation between limited stage disease and PD-L1 expression [26,29], earlier stage may be associated with a greater invasion of lymphocytes. This study has some limitations. First, the number of patients was relatively small; second, the study population was heterogeneous and included both those with limited and extensive disease. These limitations made it difficult to calculate disease-free or progression-free survival. Third, most specimens were obtained via transbronchial lung biopsy. However, this is a general limitation in clinical practice, as most SCLC patients are diagnosed at a later stage. Fourth, the lack of an independent cohort to validate the results of our study also limits the interpretation of our study results. The FDG-PET device used in our institution may be different from that of other institutions. The SUVmax assessment may differ according to type of FDG-PET machine, introducing a possible variability in SUVmax results. Future large-sample prospective studies are warranted to overcome these limitations and validate our results.