Takeshi Iwasaki1,2, Kenichi Kohashi1, Yu Toda1, Shin Ishihara1, Yuichi Yamada1, Yoshinao Oda3. 1. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Fukuoka, Japan. 2. Department of Diagnostic Pathology, Japan Community Healthcare Organization, Kyushu Hospital, 1-8-1, Kishinoura, Yahatanishi-ku, Kitakyushu, 806-8501, Fukuoka, Japan. 3. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Fukuoka, Japan. oda@surgpath.med.kyushu-u.ac.jp.
Abstract
PURPOSE: Therapies targeting the immune checkpoint molecules programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) have been explored in various malignant tumours. In this study, we examined the relationship between PDL-1, IDO1 and JAK2 expression and the roles of these signal pathways in soft tissue leiomyosarcoma (LMS). METHODS: The next-generation sequencing data of 53 patients with LMS were obtained from an online public database and were used to assess PD-L1, IDO1 and JAK2 gene amplification and mRNA expression. Then, we determined the relationship between JAK-STAT pathway activation and PD-L1 and IDO1 expression in a LMS cell line. In addition, immunohistochemical staining of 69 cases of LMS was performed for PD-L1, IDO1, TDO2 and phosphorylated JAK2 (pJAK2). RESULTS: Comprehensive gene expression analysis using microarray and RNA-Seq data revealed that PD-L1 and IDO1 mRNA expression positively correlated with JAK2 and STAT1 mRNA expression. Two of the 53 cases exhibited PD-L1 and JAK2 gene amplification; however, they were not related to their gene expression. LMS cell line analysis revealed that IFN-γ supplementation induced IDO1 and PD-L1 expression; these effects were suppressed by JAK inhibition. Immunohistochemical analysis of the resected specimens revealed that TDO2 expression positively correlated with pJAK2 (P = 0.0490) and IDO1 expression (P < 0.0001). PD-L1-positive specimens tended to express pJAK2; however, the relationship did not reach statistical significance (P = 0.1477). CONCLUSION: The results suggest the possible feasibility of the combined inhibition of PD-1/PD-L1 or IDO1 with IFN-γ-JAK-STAT pathway inhibition to treat soft tissue LMS.
PURPOSE: Therapies targeting the immune checkpoint molecules programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) have been explored in various malignant tumours. In this study, we examined the relationship between PDL-1, IDO1 and JAK2 expression and the roles of these signal pathways in soft tissue leiomyosarcoma (LMS). METHODS: The next-generation sequencing data of 53 patients with LMS were obtained from an online public database and were used to assess PD-L1, IDO1 and JAK2 gene amplification and mRNA expression. Then, we determined the relationship between JAK-STAT pathway activation and PD-L1 and IDO1 expression in a LMS cell line. In addition, immunohistochemical staining of 69 cases of LMS was performed for PD-L1, IDO1, TDO2 and phosphorylated JAK2 (pJAK2). RESULTS: Comprehensive gene expression analysis using microarray and RNA-Seq data revealed that PD-L1 and IDO1 mRNA expression positively correlated with JAK2 and STAT1 mRNA expression. Two of the 53 cases exhibited PD-L1 and JAK2 gene amplification; however, they were not related to their gene expression. LMS cell line analysis revealed that IFN-γ supplementation induced IDO1 and PD-L1 expression; these effects were suppressed by JAK inhibition. Immunohistochemical analysis of the resected specimens revealed that TDO2 expression positively correlated with pJAK2 (P = 0.0490) and IDO1 expression (P < 0.0001). PD-L1-positive specimens tended to express pJAK2; however, the relationship did not reach statistical significance (P = 0.1477). CONCLUSION: The results suggest the possible feasibility of the combined inhibition of PD-1/PD-L1 or IDO1 with IFN-γ-JAK-STAT pathway inhibition to treat soft tissue LMS.
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