This study demonstrated that SUVmax on FDG PET/CT was related to the CD8/FOXP3 ratio, representing the functionality of the tumor microenvironment, even after adjusting for tumor factors. To our knowledge, this is the first report to consider the relationship between FDG PET/CT and TIL subsets in TNBC after adjusting for confounding factors.
TNBC is an aggressive biological subtype associated with poor prognosis and a high risk of early recurrence [26, 27]. It is essential to predict a pCR after neoadjuvant chemotherapy because a pCR is a surrogate marker of prognosis in TNBC [10, 9]. TNBC is a subtype that contains the most abundant TILs in breast cancer [3]. Previous randomized trials have reported that the abundance of TILs leads to better prognosis and the therapeutic effect of neoadjuvant chemotherapy in TNBC because of high tumor immune cytolytic activity [5–8].
In the tumor microenvironment, TILs include CD8-positive T cells, FOXP3-positive T cells, natural killer cells, dendritic cells, and macrophages. There are various regulatory cell groups in the tumor stroma in addition to lymphocytes, such as bone marrow-derived inhibitory cells, tumor-associated macrophages, cancer-associated fibroblasts, and mesenchymal stem cells [4, 14]. In breast cancer, CD8-positive T cells, which are the primary components of TILs, play a critical role in the antitumor immune response. CD8-positive T cells, the so-called CTL, produce interferon gamma (IFN-γ) to attack cancer cells [1, 28]. Recent studies have reported that CTLs are associated with high pCR rates after neoadjuvant chemotherapy and better survival in TNBC [29–31]. FOXP3-positive T cells, the so-called T-reg, act in an immune-suppressive manner against tumors[13]. T-reg constitutively expresses PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and suppresses the action of effector T cells and dendritic cells [32]. Furthermore, T-reg produces cytotoxic substances (perforin and granzyme) and suppressive cytokines (interleukin-10 and transforming growth factor-β), which suppress CTL [33]. Because CTL and T-reg have paradoxical effects on tumor microenvironmental immunity, the CD8/FOXP3 ratio is considered a reliable biomarker for predicting the prognosis and the effect of neoadjuvant chemotherapy. In particular, it has been reported that a high CD8/FOXP3 ratio is related to improved disease-free survival, overall survival, and pCR rate in TNBC [18, 19, 30]. Our findings also showed a correlation between the CD8/FOXP3 ratio and pCR rate. Previously, we reported that TIL scoring based on FDG PET/CT was related to pCR [34]. Scoring of the CD8/FOXP3 ratio might predict a pCR more accurately. PD-L1 is expressed on cancer cells and tumor-infiltrating macrophages by IFN-γ and suppresses T cell activity via the PD-1/PD-L1 pathway. Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway have been demonstrated to improve progression-free survival and the pCR rate after neoadjuvant chemotherapy in TNBC [35–37].
Previous studies have reported that SUVmax on FDG PET/CT is related to clinicopathological tumor factors, such as tumor size, nuclear grade, and the Ki-67 labeling index [38]. However, SUVmax is different between each tumor, even in those with similar tumor biology, and it might be that other factors are affecting. We demonstrated that SUVmax was influenced by TILs using surgical specimens in early-stage breast cancer after adjustment for tumor factors [11]. Other studies have also reported an association between SUVmax and tumor microenvironment factors [20–22]. However, these analyses did not adjust for tumor factors affecting FDG uptake, and the correlation between SUVmax and TIL subsets is unclear.
The relationship between SUVmax and TILs is explained by glucose metabolism in the tumor microenvironment. In the tumor area, tumor cells and activated immune cells increase glucose metabolism and express glucose transporter 1 (Glut1) [39, 40]. Tumor cells and TILs compete for glucose, and the tumor microenvironment is established by the energy balance due to metabolic competition [41, 42]. FDG PET/CT is a modality that visualizes the metabolic status of glucose and is expected to identify activated TILs.
This study has some limitations. First, it has a potential limitation in that it was a retrospective study design of a small cohort from a single institution. Second, TIL subsets were evaluated using biopsy specimens because the patients received neoadjuvant chemotherapy. The findings of this study may differ from evaluations of whole tumors. Third, the evaluation method of tumor microenvironmental factors is not generalized, and the cut-off values are specific to the present study.