The defense mechanisms may play a vital role in ensuring the prosperity of certain kinds of cancer therapies, according to new research by researchers in the Stanford University School of drugs. The study showed treatments that disable cancer-promoting genes called oncogenes less difficult more lucrative in eradicating tumors in the presence of a signaling molecule secreted by kind of immune cell called a T helper cell.
The finding is essential because many drugs now being used in humans are often tested in lab animals with weakened immune systems and many human cancer therapies actually compromise a patient’s immune system.
“We may be biasing ourselves by expecting these drugs to work on their own, without factoring in the result from the immune system,” said Dean Felsher, MD, PhD, associate professor of medicine as well as pathology and the leader from the Stanford Molecular Therapeutics Program. “We’re looking for efficacy while ignoring an entire a part of biology. What we’re choosing since the best candidates might not actually be the greatest drugs for patients.”
Felsher, who is also a member of the Stanford Cancer Center, is the senior author of the study, that will be published online Oct. 28 in Cancer Cell.
Oncogenes are genes that, when mutated, contribute to the introduction of many cancers including leukemias and lymphomas. Although cancers are naturally quite complex, some types of tumors rely so completely on the game of the mutated genes that researchers have coined the word “oncogene addiction.” Blocking the effect of these oncogenes — the main focus of several current cancer therapies — can cause the tumors to shrink. For example, the drug imatinib, marketed as Gleevec, targets a vital oncogene in chronic myelogenous leukemia and gastrointestinal stromal tumors.
“Researchers and clinicians realize that blocking the activity of oncogenes can confer dramatic clinical benefit,” said Felsher. “But until recently most of us had assumed that the majority of the effects we saw on the tumor were relatively in addition to the microenvironment of the host.”
In contrast, Felsher and the colleagues found that disabling an oncogene called Myc in mice with Myc-dependent leukemias caused complete regression of tumors only in mice with intact natureal defenses. Tumors in mice with completely or partially compromised natureal defenses shrank more slowly and were left with a thousand-fold more residual disease. These tumors were also significantly prone to recur throughout the 80 days after treatment was stopped.
When the researchers investigated more closely, they found that it was the absence of a type of T cell called CD4 helper cells that was responsible for the variations in recurrence rates (28.5 percent of animals lacking CD4-positive cells had tumor recurrence vs. none in animals missing another kind of T cell called a CD8-positive cell). Following the researchers added CD4-positive cells to immunocompromised animals, the mice regained the ability to eliminate the tumor and none experienced tumor recurrence throughout the follow-up period.
Examining the tumor cells after Myc inactivation indicated that the differences in tumor regression and recurrence weren’t due to an inability of the immune-compromised animals to trigger tumor cell death (referred to as apoptosis) or to stop cells from dividing. Rather, the cells of cancer within the immunocompromised animals were less likely to slide right into a state of inactivity called senescence and, unlike within the wild-type mice, continued to recruit new blood vessels to the tumor site (a process called angiogenesis).
“This was already provocative,” said Felsher. “When the defense mechanisms was impaired, the therapy didn’t work as well. But then we went a step further. We wanted to know specifically what it involved the CD4-positive cells that influenced tumor regression and recurrence.”
They began by looking at signaling molecules secreted by immune cells. These molecules, called cytokines, relay instructions to other cells in the area to coordinate your body’s reaction to infection or disease. Felsher and his colleagues found that the expression levels of many cytokines varied between the wild-type mice and those with compromised natureal defenses. One in particular, a molecule called thrombospondin-1, was especially interesting. It is made by CD4-positive T cells, and it regulates angiogenesis.
“We knew that if we replaced CD4-positive cells in immune-compromised mice, we repaired remarkable ability to reject the tumors when Myc was inactivated,” said Felsher. “When we tried exactly the same experiment with CD4 cells that couldn’t express thrombospondin, the mice couldn’t reject the tumor.”
Therefore, the presence of thrombospondin is important to the process of tumor rejection brought on by oncogene inactivation. Felsher and the colleagues saw a similar effect inside a mouse model of another kind of leukemia that’s determined by the expression of different oncogenes, suggesting that their findings may translate to other instances of oncogene addiction. Additionally they demonstrated that wild-type mice given an immune suppressor called cyclosporine A (commonly used in human organ transplant recipients to prevent rejection) had a similar effect on angiogenesis and the ability from the tumor cells to enter senescence.
“The problem is, many treatments for patients with lymphoma and leukemia attack both the cells of cancer and also the defense mechanisms,” said Felsher. “So we need to consider this. We can’t assume that therapies that target oncogenes act independently of all of those other body. They may depend on an intact defense mechanisms.”
Although a lot of patients think that their immune systems are inherent cancer fighters, it’s not always the case, said Felsher. Rather, most cancers occur and progress in the existence of the immune system, each shaping the other. Under some conditions the defense mechanisms can actually facilitate cancer progression, during others it will help to dismantle established tumors.
“Think of the immune system like a contractor,” said Felsher. “They come in and do what they’re paid to complete. In the presence of thrombospondin, so when oncogenes are inactivated, the immune system might help destroy the cancer. In other situations it facilitates the cancer’s growth. So we must consider this very carefully.”
In addition to Felsher, other Stanford researchers involved in the study include graduate student Kavya Rakhra; former medical students Pavan Bachireddy, MD, and Andrew Kopelman, MD; postdoctoral scholar Tahera Zabuawala, PhD; former postdoctoral scholar Robert Zeiser, MD; research associate Liwen Xu, PhD; oncology instructor Alice Fan, MD; and research assistant Qiwei Yang.
The study was funded through the Burroughs Wellcome Fund, the Damon Runyon Foundation, the nation’s Institutes of Health insurance and the Leukemia and Lymphoma Society.
Stanford University Medical Center
