A New Bioassay Platform Design for the Discovery of Small Molecules with Anticancer Immunotherapeutic Activity.

Carmela Gallo,Laura Fioretto,Giuliana D’Ippolito,Marisa Saponaro,Marcello Ziaco,Emiliano Manzo,Genoveffa Nuzzo,Raffaele De Palma,Angelo Fontana,Giusi Barra

doi:10.3390/md18120604

Abstract

Immunotherapy takes advantage of the immune system to prevent, control, and eliminate neoplastic cells. The research in the field has already led to major breakthroughs to treat cancer. In this work, we describe a platform that integrates in vitro bioassays to test the immune response and direct antitumor effects for the preclinical discovery of anticancer candidates. The platform relies on the use of dendritic cells that are professional antigen-presenting cells (APC) able to activate T cells and trigger a primary adaptive immune response. The experimental procedure is based on two phenotypic assays for the selection of chemical leads by both a panel of nine tumor cell lines and growth factor-dependent immature mouse dendritic cells (D1). The positive hits are then validated by a secondary test on human monocyte-derived dendritic cells (MoDCs). The aim of this approach is the selection of potential immunotherapeutic small molecules from natural extracts or chemical libraries.

Highlights

The immune system has long been known to patrol cancer surveillance but only in the last decade the role of the immune system has been strongly reconsidered to fight cancer [1,2]
A major breakthrough in immunotherapy has been the introduction of checkpoint inhibitors to boost T cell response against cancer cells [3,4]
In consideration of the role of the Dendritic Cells (DCs)-T cell axis in the development of anti-cancer therapies, we propose an innovative approach based on the use of a growth factor-dependent immature mouse dendritic cell (D1) and a panel of tumor cell lines for the selection of primary fractions, followed by the validation on human monocyte-derived dendritic cells (MoDCs)

Summary

Introduction

The immune system has long been known to patrol cancer surveillance but only in the last decade the role of the immune system has been strongly reconsidered to fight cancer [1,2]. Immunotherapeutic approaches aiming to enforce immune response against neoplastic cells and include adoptive cell therapies, anticancer vaccines, engineered T cells with chimeric antigen receptors (CAR-T), monoclonal antibodies, and immunomodulators have been more and more exploited. A major breakthrough in immunotherapy has been the introduction of checkpoint inhibitors to boost T cell response against cancer cells [3,4]. Molecules able of activating presentation by innate immune cells are considered a suitable tools to boost the physiological immune response against cancer [5]. Dendritic Cells (DCs) represent the most efficient professional antigen-presenting cells (APC) and, in a tumoral contest, they recognize, Mar. Drugs 2020, 18, 604; doi:10.3390/md18120604 www.mdpi.com/journal/marinedrugs

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