Developing thymus-on-a-chip and cancer-on-a-chip for cancer immunotherapy

Abstract

Dr Yu-suke Torisawa is an Associate Professor at the Hakubi Center for Advanced Research at Kyoto University, Japan, who is working to develop an in vitro system to test cancer immunotherapy. He is working closely with collaborators Professor Shin Kaneko, an Associate Professor of the Kaneko Laboratory at the Center for iPS Cell Research and Application (CiRA), Kyoto University, and Dr Yuta Mishima, who is a JSPS research fellow of the same lab. The research is funded by the Japan Agency for Medical Research and Development (AMED-PRIME), JSPS KAKENHI and the Hakubi Project at Kyoto University. The researchers are developing a cancer-on-a-chip microsystem in which a vascular network is connected to a tumour-like cancer spheroid so that blood cells can be perfused through blood vessels. The idea is that this will enable interactions between cancer cells and immune cells such as T cells to be investigated. Kaneko explains the science of the relationship between T cells and iPS cells: ‘T lymphocytes are a type of white blood cell whose functions are activated by antigen-specific recognition of target cells; the T cell receptors (TCR), which enable recognition of the target antigens that are formed by gene rearrangement involving editing of a genome sequence. However, iPS cells created by reprogramming T lymphocytes (T-iPS cells) retain the TCR gene sequence of the original T lymphocytes,’ he says. ‘We have established a method of inducing re-differentiation of rejuvenated cytotoxic T cells in large quantities from antigen-specific human T-iPS cells. Moreover, we are developing the methods of making gene transduced engineered T-iPS cell (eg. CAR-T cells, TCR-T cells) to design the target specificity. As well as continuing with research to bring this technology to the clinical stage, we are progressing with research to achieve re-differentiation of the numerous other T lymphocyte subsets from antigen-specific T lymphocytes and to exploit the special characteristics of each subset for the development of immune regenerative therapy.’ The team’s project, ‘Engineering of a 3D vascularised tissue-on-a-chip using human iPSC-derived cells’, came about when Torisawa and Mishima found themselves both working at Kyoto University at the same time. ‘Mishima started working at the Kaneko Lab to work on developing genetically engineered T cells from iPS cells. So, we teamed up to develop in vitro models to generate T cells and to test cancer immunotherapy by combining the organs-on-chips technology and the iPS cell technology,’ explains Torisawa. ‘We first worked on developing 3D perfusable vascular networks using iPS cells, since vascular networks are crucial for studying blood cells and their interactions with tissues including tumours.’