Abstract 5119: Complex, 3D tissues for modeling the immune response in cancer and predicting the activity of immunotherapies
Authors: Tessa M. DesRochers, Lillia Holmes, Qi Guo, Lauren O’Donnell, Stephen Shuford, Larry Puls, Jeff Elder, Jeff Edenfield, Hal E. Crosswell
Journal: Cancer Research (2016)

Abstract The immune system plays an active role in both the prevention and the promotion of cancer dependent upon its interaction with the tumor cells. The roles of both macrophages and T-cells in cancer progression have been heavily studied over the past few years. Macrophages have been found to be either tumor promoting or tumor preventing depending upon their differentiation status and the tumor microenvironment while the homing and cell destroying capabilities of T-cells have been manipulated to effect better, more specific tumor cell cytotoxicity through the development of therapies such as chimeric antigen receptor T-cells (CAR-T cells). Unfortunately the majority of research in the area of immune-oncology has relied upon either 2D cell culture or animal models. While a large amount of information has been learned from these models, it has been well established that 2D cell culture does not mimic in vivo biology and the immune system of mouse models differs from that of humans in numerous ways including T-cell subsets, cytokine receptors, and costimulatory molecule expression. To overcome these limitations, we have developed a number of 3D in vitro tissue models including multi-cell type models of glioblastoma (GBM), breast, and ovarian cancer. Our GBM model combines tumor cells, endothelial cells, and macrophages; the ovarian cancer model includes patient-derived tumor cells and macrophages; our breast cancer model incorporates 5 cell types including tumor cells, fibroblasts, adipocytes, endothelial cells, and macrophages. We have also begun preliminary work to incorporate patient-specific T-cells into these models. Preliminary work in GBM and breast has utilized a combination of cell lines and primary cells while ovarian modeling has relied solely upon primary patient cells from either solid tumors or ascitic fluid. These models have been characterized for tumor cell viability, biomarker expression, and drug response. We have noted changes in both tumor cell viability and biomarker expression dependent upon macrophage differentiation and have also observed the reciprocal effect of tumor cells upon the macrophages. Additionally, employing multiphoton microscopy we have identified the incorporation of macrophages into the 3D microtumors. Utilizing primary patient tumor cells and immune components, we can test these models for patient-specific responses to not only traditional chemotherapeutics, but also immunotherapies such as CAR-Ts and antibody drug conjugates. Citation Format: Tessa M. DesRochers, Lillia Holmes, Qi Guo, Lauren O’Donnell, Stephen Shuford, Larry Puls, Jeff Elder, Jeff Edenfield, Hal E. Crosswell. Complex, 3D tissues for modeling the immune response in cancer and predicting the activity of immunotherapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5119.