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Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets

1
School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, 1211 Geneva, Switzerland
2
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland
3
Translational Research Center in Oncohaematology, 1211 Geneva, Switzerland
4
Department of Visceral Surgery, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
5
Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editor: Sergio Bracarda
Cancers 2021, 13(11), 2551; https://doi.org/10.3390/cancers13112551
Received: 15 April 2021 / Revised: 17 May 2021 / Accepted: 19 May 2021 / Published: 22 May 2021
Three-dimensional cancer models have gained interest from pre-clinical testing of single drugs and drug combinations. The research aim of this study was to develop a heterotypic 3D co-culture harboring selected immune cell subsets to evaluate the efficacy of a drug combination for the treatment of renal cell carcinoma. Heterotypic spheroids containing 70% cancer, 20% fibroblasts, and 10% endothelial cells were cultured in a scaffold-free system. Native or immortalized immune cells were added directly or 24 h post spheroid formation, and their infiltration was observed. This infiltration was found to be modulated by various treatment conditions. Our study revealed that heterotypic short-term 3D spheroids complemented with immune cell subsets represent a valuable tool for tumor-immune cell interaction and treatment screening platforms.
Two-dimensional cell culture-based platforms are easy and reproducible, however, they do not resemble the heterotypic cell-cell interactions or the complex tumor microenvironment. These parameters influence the treatment response and the cancer cell fate. Platforms to study the efficacy of anti-cancer treatments and their impact on the tumor microenvironment are currently being developed. In this study, we established robust, reproducible, and easy-to-use short-term spheroid cultures to mimic clear cell renal cell carcinoma (ccRCC). These 3D co-cultures included human endothelial cells, fibroblasts, immune cell subsets, and ccRCC cell lines, both parental and sunitinib-resistant. During spheroid formation, cells induce the production and secretion of the extracellular matrix. We monitored immune cell infiltration, surface protein expression, and the response to a treatment showing that the immune cells infiltrated the spheroid co-cultures within 6 h. Treatment with an optimized drug combination or the small molecule-based targeted drug sunitinib increased immune cell infiltration significantly. Assessing the therapeutic potential of this drug combination in this platform, we revealed that the expression of PD-L1 increased in 3D co-cultures. The cost- and time-effective establishment of our 3D co-culture model and its application as a pre-clinical drug screening platform can facilitate the treatment validation and clinical translation. View Full-Text
Keywords: 3D co-cultures; combination therapy; heterotypic spheroids; immune cells; immunotherapy; infiltration; PD-L1; renal cell carcinoma; sunitinib 3D co-cultures; combination therapy; heterotypic spheroids; immune cells; immunotherapy; infiltration; PD-L1; renal cell carcinoma; sunitinib
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MDPI and ACS Style

Rausch, M.; Blanc, L.; De Souza Silva, O.; Dormond, O.; Griffioen, A.W.; Nowak-Sliwinska, P. Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets. Cancers 2021, 13, 2551. https://doi.org/10.3390/cancers13112551

AMA Style

Rausch M, Blanc L, De Souza Silva O, Dormond O, Griffioen AW, Nowak-Sliwinska P. Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets. Cancers. 2021; 13(11):2551. https://doi.org/10.3390/cancers13112551

Chicago/Turabian Style

Rausch, Magdalena, Léa Blanc, Olga De Souza Silva, Olivier Dormond, Arjan W. Griffioen, and Patrycja Nowak-Sliwinska. 2021. "Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets" Cancers 13, no. 11: 2551. https://doi.org/10.3390/cancers13112551

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