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

Abstract

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.

• Authors: Stanley Borowicz, Daniel R Principe, Matthew J Dorman, Austin J McHenry, Gautam Sondarva, Sandeep Kumar, Vijayalakshmi Ananthanarayanan, Patricia E Simms, Ashley Hess, Ajay Rana
• Journal: PloS one (PLoS One) Vol. 16 Issue 6 Pg. e0252197 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34185790 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Proteinase Inhibitory Proteins, Secretory
• SPINT1 protein, human

Topics

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