Therapeutic potential of anti-VEGF receptor 2 therapy targeting for M2-tumor-associated macrophages in colorectal cancer

博士（医学）福島県立医科大

Epithelial-mesenchymal transition-converted tumor cells can induce T-cell apoptosis through upregulation of programmed death ligand 1 expression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor, and it is urgently needed to develop novel therapeutic strategies including immunotherapy. In this study, we investigated the upregulation of the programmed death ligand 1 (PD-L1) due to epithelial-mesenchymal transition (EMT) in ESCC using an in vitro treatment system with the EMT inducer, glycogen synthase kinase (GSK)-3 inhibitor, and we also analyzed the correlation of EMT and PD-L1 expression in the clinical tumor samples of both tissue microarray (TMA) samples (n = 177) and whole tissue samples (n = 21). As a result, the inhibition of GSK-3β induces EMT phenotype with upregulated vimentin and downregulated E-cadherin as well as increased Snail and Zinc finger E box-binding homeobox (ZEB)-1 gene expression. Simultaneously, we showed that EMT-converted ESCC indicated the upregulation of PD-L1 at both protein (total and surface) and mRNA levels. Of importance, we showed that EMT-converted tumor cells have a capability to induce T-cell apoptosis to a greater extent in comparison to original epithelial type tumor cells. Furthermore, the immunohistochemical stains of ESCC showed that PD-L1 expression on tumor cells was positively correlated with EMT status in TMA samples (P = .0004) and whole tissue samples (P = .0029). In conclusion, our in vitro and in vivo study clearly demonstrated that PD-L1 expression was upregulated in mesenchymal type tumors of ESCC. These findings provide a strong rationale for the clinical use of anti-PD- 1/ anti-PD- L1 monoclonal antibodies for advanced ESCC patients

Immunotherapy for esophageal squamous cell carcinoma: a review

Cancer vaccines and immune checkpoint inhibitors (ICI) have recently been employed as immunotherapies for esophageal squamous cell carcinoma (ESCC). Cancer vaccines for ESCC have yielded several promising results from investigator-initiated phase I and II clinical trials. Furthermore, a Randomized Controlled Trial as an adjuvant setting after curative surgery is in progress in Japan. On the other hand, ICI, anti-CTLA-4 mAb and anti-PD-1 mAb, have demonstrated tumor shrinkage and improved overall survival in patients with multiple cancer types. For ESCC, several clinical trials using anti-PD-1/anti-PD-L1 mAb are underway with several recent promising results. In this review, cancer vaccines and ICI are discussed as novel therapeutic strategies for ESCC