title: A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis.
abstract: Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non-small cell lung cancer. We hypothesized that combined inhibition of C5a/C5aR1 and PD-1 signaling may have a synergistic antitumor effect. The RMP1-14 antibody was used to block PD-1, and an L-aptamer was used to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer, we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis and leads to prolonged survival. This effect is accompanied by a negative association between the frequency of CD8 T cells and myeloid-derived suppressor cells within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. Our study provides support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer.Significance:Using a variety of preclinical models of lung cancer, we demonstrate that the blockade of C5a results in a substantial improvement in the efficacy of anti-PD-1 antibodies against lung cancer growth and metastasis. This study provides the preclinical rationale for the combined blockade of PD-1/PD-L1 and C5a to restore antitumor immune responses, inhibit tumor cell growth, and improve outcomes of patients with lung cancer.Cancer Discov; 7(7); 694-703. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.|University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ajona
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ortiz-Espinosa
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.
authors.forename: Haritz
authors.initials: H
authors.lastname: Moreno
authors.affiliation: Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|University of Navarra, CIMA, Program in Immunology and Immunotherapy, Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lozano
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.|University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.|University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bértolo
authors.affiliation: Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|University of Navarra, CIMA, Program in Immunology and Immunotherapy, Pamplona, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lasarte
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Vicent
authors.affiliation: Aptarion Biotech, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Hoehlig
authors.affiliation: Aptarion Biotech, Berlin, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Vater
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.|University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.|University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.affiliation: University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain. rpio@unav.es.|Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.|University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D052158:Aptamers, Peptide / Q000276:immunology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000276:immunology; D009362:Neoplasm Metastasis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D052158:Aptamers, Peptide; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D015936:Complement C5a