José Avendaño-Ortiz1, Emilio Llanos-González2, Víctor Toledano1, Rosa Del Campo3, Carolina Cubillos-Zapata4, Roberto Lozano-Rodríguez2, Ahmad Ismail2, Concepción Prados5, Paloma Gómez-Campelo2, Luis A Aguirre2, Francisco García-Río4, Eduardo López-Collazo6. 1. Innate Immunity Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Tumor Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain; Center for Biomedical Research Network, CIBEres, Spain. 2. Innate Immunity Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Tumor Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain. 3. Department of Microbiology, University Hospital Ramón y Cajal and IRYCIS, Madrid, Spain. 4. Center for Biomedical Research Network, CIBEres, Spain; Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain. 5. Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain. 6. Innate Immunity Group, IdiPAZ, La Paz University Hospital, Madrid, Spain; Tumor Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain; Center for Biomedical Research Network, CIBEres, Spain. Electronic address: elopezc@salud.madrid.org.
Abstract
BACKGROUND: Cystic fibrosis (CF) is an endotoxin tolerance (ET)-related disease. Given that increased PD-L1 has been reported in ET, its expression and physiological effects on cystic fibrosis monocytes should be studied. METHODS: We analyzed the phenotype and ex vivo response of immune system cells in 32 patients with CF, 19 of them colonized by Pseudomonas aeruginosa. An in vitro model was developed of Pseudomonas aeruginosa colonization using purified lipopolysaccharides (LPS) from one of the most prevalent strains in patients with CF (a CF-adapted Pseudomonas aeruginosa ST395 clone). Changes in the immune response, including cytokine production and T-lymphocyte proliferation, as well as expression of PD-L1, were evaluated. RESULTS: PD-L1 was overexpressed in the monocytes of patients with CF compared with healthy volunteers, and levels of this immune checkpoint were associated with Pseudomonas aeruginosa colonization. In addition, patients with Pseudomonas aeruginosa colonization showed a patent ET status, including poor inflammatory response, reduced HLA-DR expression and T-lymphocyte proliferation impairment. PD-L1/PD-1 blocking assays reverted the impaired adaptive response. Ultimately, monocytes from healthy volunteers cultured in the presence of the clinically relevant strain of Pseudomonas aeruginosa or serum collected from patients with CF colonized by Pseudomonas aeruginosa reproduced the previous observed features. CONCLUSIONS: Pseudomonas aeruginosa colonization in patients with CF was associated with PD-L1 overexpression and impaired T cell response, and LPS from this pathogen induced the observed phenotype. Our findings open new avenues for the use of anti-PD-1/PD-L1 immunotherapy in patients with CF who are colonized by Pseudomonas aeruginosa.
BACKGROUND:Cystic fibrosis (CF) is an endotoxin tolerance (ET)-related disease. Given that increased PD-L1 has been reported in ET, its expression and physiological effects on cystic fibrosis monocytes should be studied. METHODS: We analyzed the phenotype and ex vivo response of immune system cells in 32 patients with CF, 19 of them colonized by Pseudomonas aeruginosa. An in vitro model was developed of Pseudomonas aeruginosa colonization using purified lipopolysaccharides (LPS) from one of the most prevalent strains in patients with CF (a CF-adapted Pseudomonas aeruginosa ST395 clone). Changes in the immune response, including cytokine production and T-lymphocyte proliferation, as well as expression of PD-L1, were evaluated. RESULTS:PD-L1 was overexpressed in the monocytes of patients with CF compared with healthy volunteers, and levels of this immune checkpoint were associated with Pseudomonas aeruginosa colonization. In addition, patients with Pseudomonas aeruginosa colonization showed a patent ET status, including poor inflammatory response, reduced HLA-DR expression and T-lymphocyte proliferation impairment. PD-L1/PD-1 blocking assays reverted the impaired adaptive response. Ultimately, monocytes from healthy volunteers cultured in the presence of the clinically relevant strain of Pseudomonas aeruginosa or serum collected from patients with CF colonized by Pseudomonas aeruginosa reproduced the previous observed features. CONCLUSIONS:Pseudomonas aeruginosa colonization in patients with CF was associated with PD-L1 overexpression and impaired T cell response, and LPS from this pathogen induced the observed phenotype. Our findings open new avenues for the use of anti-PD-1/PD-L1 immunotherapy in patients with CF who are colonized by Pseudomonas aeruginosa.
Authors: Marta Garcia-Clemente; David de la Rosa; Luis Máiz; Rosa Girón; Marina Blanco; Casilda Olveira; Rafael Canton; Miguel Angel Martinez-García Journal: J Clin Med Date: 2020-11-24 Impact factor: 4.241
Authors: Bijean D Ford; Diego Moncada Giraldo; Camilla Margaroli; Vincent D Giacalone; Milton R Brown; Limin Peng; Rabindra Tirouvanziam Journal: Int J Mol Sci Date: 2021-03-03 Impact factor: 5.923