title: Correlation between anti-PD-L1 tumor concentrations and tumor-specific and nonspecific biomarkers in a melanoma mouse model.
abstract: Blockade of PD-L1 with specific monoclonal antibodies (anti-PD-L1) represents a therapeutic strategy to increase the capability of the immune system to modulate the tumor immune-resistance. The relationship between anti-PD-L1 tumor exposition and anti-tumor effect represents a challenge that has been addressed in this work through the identification of certain biomarkers implicated in the antibody's mechanism of action, using a syngeneic melanoma mouse model. The development of an in-vitro/in-vivo platform has allowed us to investigate the PD-L1 behavior after its blockage with anti-PD-L1 at cellular level and in animals. In-vitro studies showed that the complex PD-L1/anti-PD-L1 was retained mainly at the cell surface. The antibody concentration and time exposure affected directly the recycling or ligand turnover. In-vivo studies showed that anti-PD-L1 was therapeutically active at all stage of the disease, with a rapid onset, a low but durable efficacy and non-relevant toxic effect. This efficacy measured as tumor shrinkage correlated with tumor-specific infiltrating lymphocytes (TILs), which increased as antibody tumor concentrations increased. Both, TILS and antibody concentrations followed similar kinetic patterns, justifying the observed anti-PD-L1 rapid onset. Interestingly, peripheral lymphocytes (PBLs) behave as infiltrating lymphocytes, suggesting that these PBLs might be considered as a possible biomarker for antibody activity.
authors.affiliation: School of Pharmacy, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Contreras-Sandoval
authors.affiliation: School of Pharmacy, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Merino
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, 31008, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Vasquez
authors.affiliation: School of Pharmacy, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.affiliation: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, 31008, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.affiliation: School of Pharmacy, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Garrido
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000276:immunology; D045744:Cell Line, Tumor; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human
keywords: anti-PD-L1 mAb; biomarkers; immunomodulation; melanoma model; preclinical study