Tumor-on-a-chip offers insight into cancer-fighting cells in immunotherapy

Key Takeaways

• The “tumor-on-a-chip” recreates the body’s tumor environment in miniature, complete with blood vessels and immune cells, so researchers can “see” what helps or hinders engineered immune cells inside solid tumors.

• Adding vildagliptin, a drug currently used to treat type 2 diabetes, to the chip, allows many more CAR T cells to break through the protective tumor microenvironment and attack the tumor.

• These chips could help accelerate the development of more efficacious and safer immunotherapies for cancer patients while reducing the need for the use of other preclinical models.

For a little over two decades, chimeric antigen receptor (CAR) T cell therapy has emerged as a powerful new way to treat cancer. By extracting patients’ T cells, re-engineering them to recognize tumor antigens, and infusing them back into the body, physicians have achieved effective treatments for leukemia and lymphoma cancers.

“This approach has achieved remarkable success against blood cancers, but the same cannot be said for solid tumors, which account for over 90% of all cancers,” says Dan Dongeun Huh, professor of bioengineering at Penn’s School of Engineering and Applied Science. “The main challenge is in overcoming the tumor microenvironment (TME), a fortress-like, hostile ecosystem that actively ‘protects’ and ‘hides’ malignant cells from immune attack.”

Cancer cells are nourished by dysfunctional “leaky” blood vessels and shielded by a network of biological signals. Getting cancer-killing CAR T-cells through this fortress wall, let alone keeping them functional once inside, has been a monumental challenge.

Now, Huh and his collaborators have developed a transparent, microengineered device that houses a living, vascularized model of human lung cancer—a “tumor on a chip.” Their findings, published in Nature Biotechnology, give scientists a real-time window into how engineered immune cells interact with cancer, revealing weaknesses in the tumor’s defense and uncovering unexpected ways to help the immune cells win.

“The core concept here is to create an environment where the tumor cells behave just as they would in the human body,” says Haijiao Liu, first author and postdoctoral researcher in Huh’s BIOLines Lab. “We try to make the cells feel at home so that they ‘regain their memory’ and remember what they do, like co-opt our healthy cells and entomb themselves with the TME.”

The researchers also discovered that tumor-blood-vessel cells, endothelial cells, send chemical “come-here” signals to draw CAR T cells into the tumor, but those signals fade quickly. By adding vildagliptin, a drug approved for the treatment of type 2 diabetes and that prevents the breakdown of those signaling molecules, the team was able to strengthen that call for help and guide more immune cells to the cancer site.

Pairing the tumor-on-a-chip with multiomics technology—which integrates genomic, proteomic, and metabolic data—and powerful tools from bioinformatics and data science, Huh’s team was able to peer into the molecular biology of what CAR T cells experience inside the tumor microenvironment.

The team used this profiling to identify an enzyme (DPP4) produced by both fibroblasts and T cells as the culprit cutting short those chemical distress signals. Because DPP4’s function and inhibitors are well characterized in diabetes research, the researchers realized that an existing DPP4-blocking drug might restore communication between tumor vessels and immune cells. When they tested vildagliptin on the chip, it effectively preserved those signaling molecules that allowed more CAR T cells to follow the trail and infiltrate the tumor.

“The beauty of this system,” Huh says, “is that it’s transparent. It’s like a window into the battlefield of cancer immunotherapy inside the body. We can literally watch the CAR T cells crawl through the tumor tissue, strike their targets, and sometimes fail.”

In one instance, the team witnessed how a single T cell slips through a vessel wall, migrates across tissue, and attacks a glowing (under fluorescence imaging) cluster of tumor cells—something that, until now, could only be inferred from preclinical studies.

Their work paves the way for new CAR designs that can now be evaluated quickly and safely before reaching patients.

Another advantage of the work, says Huh is that “it is now possible to use organ-on-a-chip models of complex human disease to bring us closer to reducing our reliance on animal experiments in biomedical research.”

Huh says, “The physiological realism of our model makes it possible to generate human-relevant, high-dimensional preclinical data that allow us to probe and understand the molecular inner workings of cancer-immune interactions. New mechanistic knowledge and biological insights we gain from these data could help accelerate the development of more efficacious and safer immunotherapies for cancer patients.”

Dan Dongeun Huh is a professor of bioengineering at the University of Pennsylvania’s School of Engineering and Applied Science.

Haijiao Liu was a postdoctoral researcher in Huh’s BIOLines Lab at Penn Engineering.

Other authors include Sezin Aday Aydin, Jeehan Chang, Xuanqi Dong, Haonan Hu, Aidi Liu, Zirui Ou, Jungwook Paek, Ju Young Park, Dora Maria Racca, Se-jeong Kim, and Anni Wang of Penn Engineering; Steven M. Albelda, Joshua J. Brotman, Zeyu Chen, Soyeon Kim, Maria Liousia, Marina C. Martinez, Edmund K. Moon, Estela Noguera-Ortega, Xinyi Shi, and E. John Wherry of the Perelman School of Medicine at Penn; Wei Guo and Yumei Li of Penn Arts & Sciences; Zebin Xiao and Ellen Puré of the School of Veterinary Medicine at Penn; Yonghee Shin and Taewook Kang of Sogang University; and G. Scott Worthen of Children’s Hospital of Philadelphia; and Won Dong Lee and Joshua D. Rabinowitz of Princeton University.

This research received support from the Cancer Research Institute, the National Institutes of Health (DP2 HL127720-01, F32 DK127843, R01 CA163591, and DP1 DK113643), the National Science Foundation (CMMI-1548571), the Ministry of Trade, Industry and Energy of the Republic of Korea, the GRDC Cooperative Hub through the National Research Foundation of Korea funded by the Ministry of Science and ICT (RS-2023-00259341), the Paul Allen Foundation, Ludwig Cancer Research, and the University of Pennsylvania.