title: Increased proteinase inhibitor-9 (PI-9) and reduced granzyme B in lung cancer: mechanism for immune evasion?
abstract: Cytotoxic CD8(+) T-cells mount immune responses to cancer via cytotoxic pathways including granzyme B. Cancer cells are also known to develop immune evasion mechanisms. We hypothesised that lung cancer cells would over-express the granzyme B-inhibitor, proteinase inhibitor-9 (PI-9) and down-regulate granzyme B expression by neighbouring CD8(+) T-cells. We investigated PI-9 expression in lung cancer cell lines, and primary lung cancer cells obtained at curative lung resection from cancer patients with/without chronic obstructive pulmonary disease (COPD). Granzyme B and PI-9 expression was also determined in CD8(+) T-cells from the cancer and non-cancer areas of resected lung tissue and from bronchoalveolar lavage (BAL). We then evaluated the effects of conditioned media from lung cancer cell lines on granzyme B expression and the cytotoxic activity of CD8(+) T-cells. PI-9 was highly expressed in lung cancer cell lines. Increased PI-9 expression was also observed in primary cancer cells vs. epithelial cells from non-cancer tissue or bronchial brushing-derived normal primary large airway epithelial cells. Expression significantly correlated with cancer stage. Significantly reduced granzyme B was noted in CD8(+) T-cells from cancer vs. non-cancer tissue. Granzyme B production by CD8(+) T-cells was reduced in the presence of conditioned media from lung cancer cell lines. Our data suggest that lung cancer cells utilise their increased PI-9 expression to protect from granzyme B-mediated cytotoxicity as an immune evasion mechanism, a function that increases with lung cancer stage.
authors.affiliation: Lung Research Laboratory, Hanson Institute, Australia.
authors.forename: Cyd
authors.initials: C
authors.lastname: Soriano
authors.forename: Violet
authors.initials: V
authors.lastname: Mukaro
authors.forename: Greg
authors.initials: G
authors.lastname: Hodge
authors.forename: Jessica
authors.initials: J
authors.lastname: Ahern
authors.forename: Mark
authors.initials: M
authors.lastname: Holmes
authors.forename: Hubertus
authors.initials: H
authors.lastname: Jersmann
authors.forename: David
authors.initials: D
authors.lastname: Moffat
authors.forename: David
authors.initials: D
authors.lastname: Meredith
authors.forename: Craig
authors.initials: C
authors.lastname: Jurisevic
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: Sandra
authors.initials: S
authors.lastname: Hodge
mesh_terms: D000368:Aged; D001992:Bronchoalveolar Lavage Fluid; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002457:Cell Extracts / Q000494:pharmacology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D003602:Cytotoxicity, Immunologic; D005260:Female; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015843:Serpins / Q000378:metabolism*; D019139:Tumor Escape
chemical_list: D002457:Cell Extracts; D017077:Culture Media, Conditioned; C102316:SERPINB9 protein, human; D015843:Serpins; D053804:Granzymes