Priority Research Papers:
Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures
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Niklas K. Finnberg1, Prashanth Gokare1, Avital Lev1, Sergei I. Grivennikov2, Alexander W. MacFarlane IV3, Kerry S. Campbell3, Ryan M. Winters4, Karen Kaputa4, Jeffrey M. Farma5, Abbas El-Sayed Abbas6, Luigi Grasso7, Nicholas C. Nicolaides7 and Wafik S. El-Deiry1
1 Department of Hematology/Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
2 Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA
3 Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA, USA
4 Biosample Repository Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
5 Division of General Surgery, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
6 Division of Thoracic Surgery, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
7 Morphotek Inc., Philadelphia, PA, USA
Wafik S. El-Deiry, email:
Keywords: 3D, organoid, colorectal cancer, immune cells, biomarkers
Received: June 24, 2017 Accepted: July 20, 2017 Published: August 05, 2017
We have developed 3D-tumoroids and tumor slice in vitro culture systems from surgical tumor specimens derived from patients with colorectal cancer (CRC) or lung cancer to evaluate immune cell populations infiltrating cultured tissues. The system incorporates patient’s peripherally and tumor-derived immune cells into tumoroid in vitro cultures to evaluate the ability of the culture to mimic an immunosuppressive tumor microenvironment (ITM). This system enables analysis of tumor response to standard therapy within weeks of surgical resection. Here we show that tumoroid cultures from a CRC patient are highly sensitive to the thymidylate synthase inhibitor 5-fluorouracil (adrucil) but less sensitive to the combination of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (Lonsurf). Moreover, re-introduction of isolated immune cells derived from surrounding and infiltrating tumor tissue as well as CD45+ tumor infiltrating hematopoietic cells displayed prolonged (>10 days) survival in co-culture. Established tumor slice cultures were found to contain both an outer epithelial and inner stromal cell compartment mimicking tumor structure in vivo.
Collectively, these data suggest that, 3D-tumoroid and slice culture assays may provide a feasible in vitro approach to assess efficacy of novel therapeutics in the context of heterogeneous tumor-associated cell types including immune and non-transformed stromal cells. In addition, delineating the impact of therapeutics on immune cells, and cell types involved in therapeutic resistance mechanisms may be possible in general or for patient-specific responses.
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