A study published earlier this week in Molecular Carcinogenesis describes significant progress toward a more complete humanized mouse model. By using not only human hematopoietic stem and progenitor cells (HSPCs), but also mesenchymal stem cells (MSCs) to seed a human immune system in mice, researchers were able to grow an immune system that much more faithfully represented the conditions of a human immune system, leading to more realistic immunotherapy test results in these models.
"We need both kinds of cells. HSPCs give rise to blood cells like T cells and B cells; MSCs seem to assist the bone marrow to generate more of those blood cells and also other cell types such as macrophages and fibroblasts. We've known from transplantation in humans that these sides of the immune system cooperate. Now we see something similar when engrafting human immune systems in mice," says Antonio Jimeno, M.D., Ph.D., director of the Head and Neck Cancer Clinical Research Program at the University of Colorado Cancer Center.
"There's not a perfect model and all models have limitations, but it's important to try to move the field forward. Sometimes you get a touchdown and sometimes you just go one yard at a time. This study describes many of these one-yard runs as we've been incrementally learning over the course of years," says J. Jason Morton, Ph.D., assistant research professor in the CU School of Medicine Division of Medical Oncology, and the paper's first author.
The use of both HSPCs and MSCs produced mice with almost twice the percentage of human immune cells in their bone marrow, compared to mice engrafted with HSPCs alone. Increased bone marrow immune cells in turn produced 9- to 38-fold higher levels of mature human immune cells circulating in the blood system. And immune cells were not only increased in circulation, but were enriched inside of tumors. Specifically, T cells, B cells and macrophages in the tumors of mice that had been developed in this way were 2-8 times higher than in models that were developed with HSPCs alone.
The group is now working to take their humanized mouse model a step further, using tumor sample and blood stem cells from the same patient. If successful, the model could someday allow doctors to preview how an immunotherapy might work with a specific patient, guiding treatment decisions.