Project Summary
Modeling the native dynamic interaction between tumor and immune system is crucial for developing and testing
new precision immunotherapeutic strategies, as well as predicting clinical response to innovative cancer
treatments, such as immune checkpoint blockade therapy. Tremendous efforts have been focused on the
development of current patient-derived cancer models including 2D primary cancer cell cultures, 3D spheroid
and organoid cultures, and patient-derived xenografts (PDX). However, these models fall short of reproducing
patients’ native cancer-immune interaction dynamics, largely due to their low throughput, lengthy culture periods
(several weeks), lack of tumor microenvironmental components (e.g. immune cells), and/or scaffolding that
interferes with T cell migration and cellular interaction.
Our overall objective here is to acoustically assemble novel patient organoids that represent the
microenvironmental components of a patient’s tumor in order to screen immune cell infiltration and cytotoxicity
dynamics in a high-throughput and time efficient manner. Our preliminary research demonstrated the acoustic
assembly of about 6,000 scaffold-free homotypic tumor spheroids in one day using standard cell lines. The
proposed project aims to (1) acoustically assemble a large number of heterotypic organoids using patient tumor
samples; (2) monitor the dynamic T cell interaction with acoustically-engineered patient organoids trapped on a
pillar array using our microfluidic high throughput, time-lapse single cell imaging approach; and (3) determine T
cell tumor dynamic infiltration and cytotoxicity or exhaustion.
We expect the proposed work will yield three outcomes. First, a novel acoustic organoid model will be developed
to form a high number of heterotypic patient tumor organoids. Second, this platform will be employed to study T
cell tumor infiltration dynamics and exhaustion in immunosuppressive microenvironments that closely mimic the
patient tumor. Third, this platform will allow high-throughput and high-efficiency screening of agents (e.g. immune
checkpoint inhibitors) for the development of novel cancer immunotherapy strategies to treat solid tumors.