HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization.
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...
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2021
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oai:doaj.org-article:25fe873de866459c8a595831290f24952021-12-02T20:03:49ZHAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization.1932-620310.1371/journal.pone.0252197https://doaj.org/article/25fe873de866459c8a595831290f24952021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252197https://doaj.org/toc/1932-6203Non-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.Stanley BorowiczDaniel R PrincipeMatthew J DormanAustin J McHenryGautam SondarvaSandeep KumarVijayalakshmi AnanthanarayananPatricia E SimmsAshley HessAjay RanaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252197 (2021) |
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Medicine R Science Q Stanley Borowicz Daniel R Principe Matthew J Dorman Austin J McHenry Gautam Sondarva Sandeep Kumar Vijayalakshmi Ananthanarayanan Patricia E Simms Ashley Hess Ajay Rana HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization. |
| description |
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. |
| format |
article |
| author |
Stanley Borowicz Daniel R Principe Matthew J Dorman Austin J McHenry Gautam Sondarva Sandeep Kumar Vijayalakshmi Ananthanarayanan Patricia E Simms Ashley Hess Ajay Rana |
| author_facet |
Stanley Borowicz Daniel R Principe Matthew J Dorman Austin J McHenry Gautam Sondarva Sandeep Kumar Vijayalakshmi Ananthanarayanan Patricia E Simms Ashley Hess Ajay Rana |
| author_sort |
Stanley Borowicz |
| title |
HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization. |
| title_short |
HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization. |
| title_full |
HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization. |
| title_fullStr |
HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization. |
| title_full_unstemmed |
HAI-1 is an independent predictor of lung cancer mortality and is required for M1 macrophage polarization. |
| title_sort |
hai-1 is an independent predictor of lung cancer mortality and is required for m1 macrophage polarization. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/25fe873de866459c8a595831290f2495 |
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