Association of PD-L1 and IDO1 expression with JAK-STAT pathway activation in soft-tissue leiomyosarcoma

J Cancer Res Clin Oncol. 2021 May;147(5):1451-1463. doi: 10.1007/s00432-020-03390-9. Epub 2020 Sep 20.

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.

Keywords: Indoleamine 2,3-dioxygenase 1; JAK–STAT pathway; Programmed death ligand 1; Soft tissue leiomyosarcoma.

MeSH terms

  • B7-H1 Antigen / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Expression / genetics
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics*
  • Janus Kinase 2 / genetics*
  • Leiomyosarcoma / genetics*
  • Male
  • Middle Aged
  • RNA, Messenger / genetics
  • STAT1 Transcription Factor / genetics*
  • Signal Transduction / genetics*
  • Soft Tissue Neoplasms / genetics*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • indoleamine 2,3-dioxygenase 1, human
  • JAK2 protein, human
  • Janus Kinase 2