Preclinical studies in cancer immunotherapy, such as those involving checkpoint blockade are usually conducted and validated in mice; however, rodent immune responses do not faithfully mimic those observed in humans. The overall goal of this project is to leverage recent advances in human organ-on-chip technology to create a human lymph-node-on-chip (hLN-on-chip) that exhibits complex human immune functionality. For maximum applicability, we have started with human peripheral blood mononuclear cells (PBMC) such that these devices may be widely used as non-invasive surrogates for patient testing. We have optimized matrix, cellular composition, chip design and microfluidic perfusion to induce B cell clusters reminiscent of follicles found in the lymph node. T and B cell function is maintained in the hLN-on-chip as evidenced by IL-2 and immunoglobulin M production in response to heat killed formalin fixed Staph aureus Cowan I (SAC), commonly used to induce a T cell dependent antibody response. Current studies are focused on defining the alterations in sensitivity and activity of the T cells. For instance, lymph node resident T and B cells are known to be polarized. Thus, we have tested if coinhibitory receptors such as CTLA-4, known to be important in anti-tumor immunity are also polarized under tissue like conditions. We also present preliminary data on optimizing the perfusion of the lymphocyte parenchyma with microengineered channels lined with lymphatic and vascular endothelial cells to model antigen delivery and immune cell trafficking. These devices will enable near real-time assessment of secreted factors, cell trafficking and high-resolution imaging of dynamic cellular interactions that occur in the human lymph node, and hence, they should prove invaluable in studying human cancer response to anti-cancer immunotherapies in the future.
Citation Format: Girija Goyal, Donald Ingber. A microengineered human lymph node-on-a-chip to study cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B102.
- ©2016 American Association for Cancer Research.