Sometimes a breakthrough in scientific research requires taking a view contrary to traditional wisdom. Such is the case with Zuoming Sun, Ph.D., of City of Hope and Noah Isakov, Ph.D., of Ben-Gurion University of the Negev, who are exploring the possibility that boosting the immune system to fight cancer can in some instances have the unintended consequence of being harmful to the patient.
The human immune system is naturally capable of killing cancer cells. But mutations and other abnormalities handicap or neutralize it, making the immune system insufficient and ineffective. In 2018, the Nobel Foundation awarded the Nobel Prize in Physiology or Medicine to two scientists who “showed how different strategies for inhibiting the brakes on the immune system can be used in the treatment of cancer.” Essentially, each Laureate discovered a protein that hinders the immune system’s ability to attack a tumor and then developed a way to clear that roadblock, giving the immune system a jolt in the process.
“Currently there is a lot of investment being made to study how to stimulate the immune system to kill cancer cells,” said Sun, an immunology expert and professor in the Department of Molecular Imaging & Therapy at the Diabetes & Metabolism Research Institute of City of Hope. But Sun argues that there is evidence that in certain circumstances boosting the immune system actually encourages cancer cell growth. “We’re trying to understand how this phenomenon works,” he said. “Why under these circumstances — in this case, when a TCF-1 gene mutation is involved — the immune system, when stimulated, actually promotes cancer growth.”
Sun, who earned his Ph.D. in molecular biology at Duke University, joined City of Hope in 2007 after six years in the Department of Immunology at University of Illinois. He has expertise in the signaling mechanisms that control T cell activation, development, differentiation and survival. Isakov, his partner in the new study, is a professor in the Department of Microbiology, Immunology & Genetics at Ben-Gurion University of the Negev in Beer Sheva, Israel. He has focused much of his research on oncogenesis, cancer immunobiology and cell signaling.
“We are out of fashion,” Sun said, “because everybody else is trying to boost the immune system to reject cancer. But we need to be careful what we do, because under certain circumstances a boosted immune system actually can have the opposite effect, it can damage the patient. We need to find out clinically which specific criteria and conditions are actually bad for these kinds of therapies so we can avoid using them. Or, when a therapy does tend to have a negative effect, how we can prevent it.”
Sun and Isakov’s collaboration is the result of a grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, which was established in 2016 by a generous gift from the Harvey L. Miller Family Foundation to support the exchange of ideas, strategies and therapies between City of Hope and Israeli investigators sponsored by the Israel Cancer Research Fund. The two scientists had never met before landing the Barron Cancer Research Scholars’ grant, but they’ve been familiar with each other’s work for nearly 20 years.
“There was no mechanism for us to meet each other,” Sun said. “So when I saw the Barron program opportunity, I said, ‘Oh, this is the perfect time, we should work together to solve this problem.’ We both have expertise in how the immune system works. Noah is an expert in how signaling molecules regulate T cell function, so he can help us understand what the signaling mechanism may be that is responsible for the immune system promoting cancer growth.”
Lymphoma can be any one of dozens of cancers that originates in the immune system, and it is the most common type of blood cancer. The body must activate T cells to initiate immune responses to battle cancer, but mutations of the T cell factor 1 (TCF-1) gene in immune cells can lead to lymphoma in the thymus. Sun and Isakov are striving to understand precisely how TCF-1 functions in the development of lymphoma so that they can develop new therapies for treating those cancers.
Specifically, the researchers have completed studies with mice where, when TCF-1 was deleted, thymic lymphoma increased in frequency. This has led them to suspect that TCF-1 plays a role in regulating both intrinsic genetic factors and the immune system’s response to extrinsic environmental factors in the service of preventing the development of cancer. They plan to do further studies to better understand how intrinsic and extrinsic factors interact with each other to foster cancer growth.
Sun and Isakov are attacking the problem from two directions: via the immune system and via the cancer cells. When the immune system is stimulated, the immune response is divided into different types, so they’re studying which types of response actually drive the progression of cancer and why. “The hypothesis we’re going to test,” Sun said, “is that those immune cells, when stimulated, produce certain proteins and become T cell effectors that can promote cancer growth.” They already have evidence that when they take serum from immune system-stimulated mice, the serum can then be used to stimulate cancer growth. But they don’t yet know what in the serum does this.
Their other approach involves trying to figure out the mechanism that causes cancer cells with the TCF-1 gene mutation to proliferate after stimulation by the immune system. One or both avenues of study could lead to important discoveries in the effort to develop more effective tools for fighting cancer.
“This is an opportunity to bring together the expertise from two different countries, two different cultures,” said Sun, who considers the Barron program funding critical to advancing his work. “We can learn from each other academically and combine our expertise to solve scientific questions.”