{"doi":"10.1371/journal.pone.0252197","title":"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.","journal":"PLoS ONE","year":2021,"id":198484,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":267413,"name":"Daniel R. Principe","orcid":"0000-0003-4355-6597","position":1,"is_corresponding":false},{"id":267416,"name":"Matthew J. Dorman","orcid":"0000-0001-7064-6163","position":2,"is_corresponding":false},{"id":773678,"name":"Austin McHenry","orcid":"0000-0001-8053-5192","position":3,"is_corresponding":false},{"id":471252,"name":"Gautam Sondarva","orcid":"0000-0002-9389-2815","position":4,"is_corresponding":false},{"id":267414,"name":"Sandeep Kumar","orcid":"0000-0002-2376-6469","position":5,"is_corresponding":false},{"id":545656,"name":"Vijayalakshmi Ananthanarayanan","orcid":"0009-0001-3993-4404","position":6,"is_corresponding":false},{"id":773679,"name":"Patricia Simms","orcid":"0000-0002-7257-9627","position":7,"is_corresponding":false},{"id":774338,"name":"Ashley Hess","orcid":null,"position":8,"is_corresponding":false},{"id":252071,"name":"Ajay Rana","orcid":"0000-0003-0951-2566","position":9,"is_corresponding":false},{"id":773677,"name":"Stanley Borowicz","orcid":"0000-0002-5664-9226","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:50:31.857233Z","pmid":"34185790","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}