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.
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Change history
24 November 2020
A Correction to this paper has been published: https://doi.org/10.1007/s00432-020-03466-6
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Acknowledgements
We appreciate the Research Support Center, Graduate School of Medical Sciences, Kyushu University, for providing the experimental devices. We would also like to thank I. Kinoshita at Kyushu University Hospital, for helpful discussions. We additionally thank M. Tomita and M. Nakamizo at the Department of Anatomic Pathology, Kyushu University and M. Kumazoe at the Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, for providing technical support. We also acknowledge the English language review by Enago (www.enago.jp).
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TI, KK and YO designed this study and wrote the manuscript. TI, YT and SI performed the experiments. TI, KK, YY and YO performed histological re-evaluation of the samples and confirmed the diagnosis. TI and YO supervised the experiments.
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This study was conducted in accordance with the principles of the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Kyushu University (No. 29-429 and 29-625).
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432_2020_3390_MOESM1_ESM.pdf
Supplemental Fig. S1 (PDF 394 kb) Of the 53 patients with leiomyosarcoma, a) two exhibited programmed death ligand 1 (PD-L1) gene amplification. b) No patient displayed indoleamine 2,3-dioxygenase-1 (IDO1) gene amplification. c) The same two patients with PD-L1 amplification also exhibited AK2 amplification.
432_2020_3390_MOESM2_ESM.pdf
Supplemental Fig. S2 (PDF 43568 kb) TAT3 inhibitor did not block interferon-gamma (IFN-γ)-induced programmed death ligand 1 (PD-L1) expression. a) TC616 cells were treated with or without IFN-γ and a STAT3 inhibitor. STAT3 inhibitor suppressed cell proliferation. b) PD-L1, IDO1 and TDO2 mRNA expression was determined via real-time PCR. (n = 3; Tukey’s honestly significant difference test). STAT3 inhibitor did not inhibit IDO1, PD-L1 or TDO2 mRNA expression. c) Western blotting showed STAT3 inhibitor did not inhibit PD-L1 and TDO2 protein expressions but reduced IDO1 protein expression. HSP90 was included as a loading control.
432_2020_3390_MOESM3_ESM.pdf
Supplemental Fig. S3 (PDF 46676 kb) Representative immunohistochemical images of programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan-2,3 dioxygenase (TDO2) and phosphorylated JAK2.
432_2020_3390_MOESM4_ESM.pdf
Supplemental Fig. S4 (PDF 383 kb) Overall and progression-free survival, as classified by programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO1) and phosphorylated JAK2 (pJAK2) expression. The Kaplan–Meier method and Wilcoxon test were used to evaluate statistical significance. Patients with low pJAK2 expression exhibited longer overall survival, albeit without significance. PD-L1 and IDO1 expression was not related to overall or progression-free survival.
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Iwasaki, T., Kohashi, K., Toda, Y. et al. Association of PD-L1 and IDO1 expression with JAK–STAT pathway activation in soft-tissue leiomyosarcoma. J Cancer Res Clin Oncol 147, 1451–1463 (2021). https://doi.org/10.1007/s00432-020-03390-9
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DOI: https://doi.org/10.1007/s00432-020-03390-9