HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization

PLoS One. 2021 Jun 29;16(6):e0252197. doi: 10.1371/journal.pone.0252197. eCollection 2021.


Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Though immune checkpoint inhibitors (ICIs) have revolutionized lung cancer therapy in recent years, there are several factors limiting the therapeutic efficacy of ICI-based immunotherapy in lung cancer. Recent evidence suggests that one such mechanism is the phenotypic shift of tumor-infiltrating macrophages away from an anti-tumor M1 phenotype and towards an anti-inflammatory and tumor-permissive M2 phenotype. Though this phenomenon is well documented, the means through which the lung tumor microenvironment (TME) usurps macrophage function are poorly described. Hepatocyte growth factor (HGF) is a known driver of both lung cancer pathobiology as well as M2 polarization, and its signaling is antagonized by the tumor suppressor gene HAI-1 (SPINT1). Using a combination of genomic databases, primary NSCLC specimens, and in vitro models, we determined that patients with loss of HAI-1 have a particularly poor prognosis, hallmarked by increased HGF expression and an M2-dominant immune infiltrate. Similarly, conditioned media from HAI-1-deficient tumor cells led to a loss of M1 and increased M2 polarization in vitro, and patient NSCLC tissues with loss of HAI-1 showed a similar loss of M1 macrophages. Combined, these results suggest that loss of HAI-1 is a potential means through which tumors acquire an immunosuppressive, M2-dominated TME, potentially through impaired M1 macrophage polarization. Hence, HAI-1 status may be informative when stratifying patients that may benefit from therapies targeting the HGF pathway, particularly as an adjuvant to ICI-based immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Immunotherapy / methods
  • Lung / metabolism
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality*
  • Macrophage Activation / physiology
  • Macrophages / metabolism*
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Signal Transduction / physiology
  • THP-1 Cells
  • Tumor Microenvironment / physiology


  • Proteinase Inhibitory Proteins, Secretory
  • SPINT1 protein, human