Tumor organoids as a personalized model of human cancer

Abstract

Tumor organoids are 3D cultures of cancer cells. Research into the applications of tumor organoids as a model system for cancer has received great interest. Here, we critically evaluate which opportunities this model systems offers, and which challenges still need to be overcome. In chapter 1, we describe the resemblance of organoids and the tumors they are derived from, and culture success rates for organoids of various tumor types. Organoids are compared to cell lines and patient-derived xenografts. We offer a perspective on potential applications for individualized medicine. In chapter 2, we make the connection with immunotherapy. Although the efficacy of immunotherapy is high, many patients do not respond to treatment. We discuss how genetic analyses can be used to identify those patients that benefit most from treatment. In chapter 3, we generate and characterize organoids of 3 different neuroendocrine carcinomas (NEC). Few preclinical models exist for this rare and understudied tumor type. These patients were treated with everolimus and cisplatin, and clinical response matches drug response of organoids. This chapter shows the potential of organoids to model rare tumors. In chapters 4 and 5, organoid models are expanded by the inclusion of immune cells. T cells from peripheral blood of cancer patients are co-cultured with tumor organoids from the same patient. This leads to tumor recognition by T cells in a subset of patients. These T cells specifically attack tumor organoids, but ignore healthy colon or lung organoids. This offers the potential to model the interaction between immune cells and cancer cells at the level of the individual patient. In chapter 6, we critically evaluate lung cancer organoids. Establishment of organoids from intrapulmonary tumors is complicated by the growth of normal airway organoids. We describe that this often leads to contamination of cultures by normal airway organoids. It is essential to determine the purity of tumor organoid cultures. We systematically describe the suitability of various methods to do so. The eventual culture success of pure lung cancer organoids is 17%, making it difficult to use this for personalized medicine. In chapter 6 we determine the suitability of organoids to predict a tumor’s sensitivity to chemotherapy. We find that sensitivity of colon cancer to irinotecan-based therapies can be predicted very well. In contrast, there is no predictive value for oxaliplatin-based therapies. This indicates that the use of tumor organoids In chapter 8 we define the role of our developed T cell – organoid co-culture system in the context of a clinical study. We study in detail a patient with two synchronous tumors, that differ in response to immunotherapy. We see that autologous T cells only recognize organoids from the sensitive tumor. We do not see differences between the two tumors when T cells specific to a model antigen are used. We describe the value and possible limitations of these different experimental setups. We conclude that organoid – T cell co-culture systems can be useful if the research question takes into account the limitations of a reductionist model system.