Oncotarget

Research Papers:

Correlation between anti-PD-L1 tumor concentrations and tumor-specific and nonspecific biomarkers in a melanoma mouse model

Ana M. Contreras-Sandoval, María Merino, Marcos Vasquez, Iñaki F. Trocóniz, Pedro Berraondo and María J. Garrido _

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Oncotarget. 2016; 7:76891-76901. https://doi.org/10.18632/oncotarget.12727

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Abstract

Ana M. Contreras-Sandoval1, María Merino1, Marcos Vasquez2, Iñaki F. Trocóniz1, Pedro Berraondo2,*, María J. Garrido1,*

1School of Pharmacy, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain

2Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, 31008, Spain

*These authors contributed equally to this work

Correspondence to:

María J. Garrido, email: [email protected]

Keywords: immunomodulation, anti-PD-L1 mAb, preclinical study, melanoma model, biomarkers

Received: May 13, 2016     Accepted: October 11, 2016     Published: October 18, 2016

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.


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