A tumor consists of different groups of cancer cells, each with its own genetic history. They’re like family members in one big family tree. These different groups are called subclones. The fact that tumors contain multiple subclones had already been discovered, but it was still unclear whether those subclones displayed fundamentally different behavior when facing the immune system. “We wanted to find out if the variations between subclones directly affects the way the immune system can recognize cancer cells,” says researcher Krijn Dijkstra. “That could help explain why immunotherapy often only clears part of the tumor.”
The researchers decided to invatigate this in organoids, small 3D cultures of tumor cells grown directly from fresh tumor samples of three patients with lung cancer. They grew about 25 mini-tumors per patient, from different regions of each tumor. “This was quite a technical challenge,” Dijkstra says. “The cells are taken straight from the tumor and need to grow into separate subclones in the lab, where they need to survive long enough to be subjected to tests with immune cells. It took a long time before that was even possible.” In fact, this only proved possible now, thanks to the unique combination of advanced organoid techniques and immune cells from the same patient.
The mini-tumors were then exposed to immune cells from the same patient. Some subclones triggered a strong immune reaction, while others did not respond at all. “It’s fascinating that tumors can contain both immune-sensitive and immune-resistant cell populations living side by side,” Dijkstra says. “This offers a broader perspective on the tumor as a dynamic ecosystem.”
By comparing the DNA of the mini-tumors, the researchers discovered that the immune-sensitive and immune-resistant cells belonged to different genetic families. These families not only look different genetically, but also behave differently when facing immune cells.
“This is the first time we have been able to directly show, per individual mini-tumor, that cancers contain subpopulations that are inherently better at evading the immune system,” Dijkstra says. “And that the difference between subpopulations is inside the cells themselves, not just caused by their surroundings.”
This research was an intensive collaboration between the research groups of Emile Voest (Netherlands Cancer Institute), Charles Swanton (the Francis Crick Institute), and Sergio Quezada. The results were published in the scientific journal Cancer Cell.
Research at the Netherlands Cancer Institute is financially supported by KWF Dutch Cancer Society and the Antoni van Leeuwenhoek Foundation.