PD-L2 overexpression on tumor-associated macrophages is one of the predictors for better prognosis in lung adenocarcinoma

Med Mol Morphol. 2023 Dec;56(4):250-256. doi: 10.1007/s00795-023-00361-0. Epub 2023 Jul 4.


Immunotherapies that target programmed cell death protein 1 (PD-1) signals are standard therapies for advanced-stage lung cancer, and the expression of programmed death-ligand 1 (PD-L1) in cancer tissue predicts immunotherapy efficacy. Although programmed death-ligand 2 (PD-L2) is expressed in cancer cells and macrophages, similar to PD-L1, its significance in lung cancer is unclear. Double immunohistochemistry analyses using anti-PD-L2 and anti-PU.1 antibodies were carried out on tissue array sections from 231 cases of lung adenocarcinoma, and PD-L2 expression in macrophages was evaluated. High PD-L2 expression in macrophages was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) and observed more often in females, non-heavy smokers, and patients with epidermal growth factor receptor (EGFR) mutations and those at a lower disease stage. Significant correlations were found more frequently in patients with EGFR mutations. Cell culture studies revealed that cancer cell-derived soluble factors induced PD-L2 overexpression in macrophages, suggesting the involvement of the JAK-STAT signaling pathway. The present findings suggest that PD-L2 expression in macrophages predicts PFS and CSS in lung adenocarcinoma without immunotherapy.

Keywords: Adenocarcinoma; Lung cancer; Macrophage; PD-L2; Tumor microenvironment.

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / pathology
  • B7-H1 Antigen
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Lung Neoplasms* / diagnosis
  • Lung Neoplasms* / genetics
  • Tumor-Associated Macrophages / metabolism
  • Tumor-Associated Macrophages / pathology


  • B7-H1 Antigen
  • ErbB Receptors
  • PDCD1LG2 protein, human