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  • br Materials and methods br Results br Discussion

    2019-08-26


    Materials and methods
    Results
    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 [22], 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 [24]. 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 [[12], [13], [14], [15], [16],[26], [27], [28], [29]]; 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,[34], [35], [36], [37], [38]], while others found it to be associated with poor prognosis [27,[39], [40], [41], [42], [43], [44], [45], [46]]. 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.