Back to the Future
Long before biologists had the ability to transfer human cancer cell lines into immune-compromised mice, their approach was somewhat more basic.
They transferred murine tumors into a mouse whose genetic background was similar to that of the tumor host. These so-called syngeneic (or syngenic) models provided lots of advantages. They were cheap to produce and plentiful enough so researchers could conduct studies with sufficient statistical power. The “apples-to-apples” transplants also sidestepped the nagging problem of tissue rejection.
Unfortunately, while scientists assembled a lot of data about tumors in mice, the models weren’t clinically relevant to human disease. The inbred mice lacked genetic complexity and the models were poor predictors of drug responses in cancer patients. So the field turned to other transplant models and genetically engineered mouse models to test their novel therapies and to study cancer pathogenesis.
But to quote Carl Sagan, “If you wait long enough, everything changes.” Though never completely out of vogue, syngeneic mouse models have re-emerged as a hot avenue for cancer science, used alongside another promising tool that patient-derived xenotransplant (PDX) models constitute to enhance our understanding of this incredibly complicated, heterogeneous disease.
Because they retain intact immune systems, syngeneic mouse models created using a variety of hematological and solid tumors—leukemia, multiple myeloma, lung, colon and breast cancer to name a few—can be particularly relevant for studies of so-called targeted therapies, either used alone or in combination with other drugs that assist the immune system in seeking out and destroying cancer cells.
One such example would be the histone deacetylase inhibitors, a diverse class of anticancer compounds that interfere with a number different mechanisms driving tumor development. There are many other examples of cancer treatment that benefit from being tested in an immunocompetent environment, including ones that block proteins that inhibit immune system cells, freeing up those cells to boost the immune system's ability to fight tumors.
The growing popularity of syngeneic models reflects how far we have come in our understanding of the human immune system—an intricate army of cells that are as complicated—if not more so—than the disease that oncologists have been trying to conquer.
For instance, researchers have a much better understanding today of the innate system—the first line of defense against viruses and bacteria—and the target of a number of these innovative cancer therapies.
One such example would be natural killer (NK) cells and subsets of NK cells, which in various ways act as first responders by rapidly containing and clearing infection, responding to tumor formation and secreting immunomodulatory cytokines that drive the adaptive immune response.1
This latter function is of particular interest right now in cancer research, so one can appreciate that our first glimpse of these components of an “ancient” arm of the immune system was only about 30 years ago, not long after scientists hypothesized that they existed.
The adaptive immune system of “helper” CD4+ T cells and “killer” CD8+ T cells working in concert to kill cancer cells is also a much more complicated artillery than we could have appreciated 30 years ago; different subsets of T cells have very specific and different functions, both on the cellular and antibody fronts.
With our increasing understanding of basic human immunology have come breakthroughs in our understanding of how cancer evades the immune system, and the development of novel immunotherapies designed specifically to break through that shield.2
Will these new classes of drugs be the much-awaiting magic bullets we all crave? Who knows? But it’s worth noting that scientists have also used their expanding knowledge of human immunology to tweak syngeneic mouse models to their liking, and design studies with endpoints that are more relevant to how the immune system impacts human tumor development. Some analysts predict that by 2023 up to half of all cancer treatments will be immunomodulatory.
Of course, the use of syngeneic models doesn’t mean we will see a decline in the use of PDX models. If anything, science is showing us that we will likely need multiple mouse models, with their unique attributes, to bring new and more effective therapies to the clinic for testing.