Associação Portuguesa de Investigação em Cancro
Assessing Novel Antibody-Based Therapies in Reconstructive 3D Cell Models of the Tumor Microenvironment
Assessing Novel Antibody-Based Therapies in Reconstructive 3D Cell Models of the Tumor Microenvironment
The therapeutic landscape in breast cancer has benefited from the development of variate antibody-based therapies. Yet, pre-clinical models capable of recapitulating the complex crosstalk within the tumor microenvironment (TME) are needed to properly address the effect of such therapies. In this work, we devised cell models able to accommodate different cell populations (3D-3), by adding stromal and immune components to multicellular tumor spheroids. The models were microencapsulated in alginate and kept under stirred conditions, to recreate critical hallmarks of the TME. Challenging 3D-3 models with antibody-drug conjugates (ADCs) induced a specific toxicity towards HER2+ tumor cells, while maintaining the viability of the stromal component. In addition, the use of a blocking antibody against colony-stimulating factor 1 receptor (CSF1R) caused a decrease in anti-inflammatory and immunosuppressive markers in immune cells. As such, it was possible to demonstrate 3D-3 models as suitable tools to assess the potential of different antibody-based therapeutic agents, directed against targets present at the TME.
Giacomo Domenici*1,2, Nuno F. Lopes*1,2, Gonçalo Trindade1,2, Isabella Ramella Gal1,2, Joan Miret Minard1,2, Sofia P. Rebelo1, Catarina Freitas1,2, Nádia Duarte1,2, Catarina Brito1,2
1 - iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
2 - Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal.
3 - Department of Chemical, Biological and Environmental Engineering, Universitat Autònoma de Barcelona, Plaça Cívica, 08193 Bellaterra, Spain.
* Equal contribution
Abstract:
Targeted, combinatorial, and immunomodulatory therapies, such as antibody-drug conjugates (ADCs) and immunomodulatory antibodies (Abs), are powerful weapons against tumor cells and immune cells within the tumor microenvironment (TME). Therefore, the evaluation of such therapies should be conducted in pre-clinical models able to recapitulate the complex cellular and molecular crosstalk of the TME. To build-in critical hallmarks of the TME, a breast cancer heterotypic 3D cell model (3D-3) is devised using a microencapsulation strategy with an inert biomaterial (alginate) and agitation-based cultures. Both stromal and immune components are added to multicellular tumor spheroids, therefore fostering cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) immunomodulatory interactions. The potential of the methodology to assess Ab-based therapies is then addressed by employing a series of anti-HER2-based ADCs. ADCs induced tumor-cell specific cytotoxicity toward HER2+ breast cancer spheroids while sparing HER2-negative CAFs. In addition, an immunomodulatory blocking Ab against colony-stimulating factor 1 receptor (CSF1R) decreases the expression of immunosuppressive and anti-inflammatory markers in TAMs, like what is previously observed upon in vivo α-CSF1R administration. Collectively, the human TME-based 3D-3 cell model is a suitable tool to evaluate the anti-tumor and immunomodulatory potential of novel antibody-based therapies directed against TME targets, such as cancer cells and macrophages.
Advanced biology
