May 9, 2016 | by City of Hope
A protein that helps protect tumor cells from the immune system may one day play a role in their destruction.
According to a new study published in the prestigious scientific journal, Immunity, scientists at City of Hope have unlocked a key component of STAT3 activation, a gene that has long been associated with tumor cell growth and anti-tumor immune suppression. By exploring how STAT3 is activated in B cells, a major type of immune cell, Chunyan Zhang, Ph.D., and colleagues have identified a novel target for cancer therapy.
“It is known that STAT3 is critical for the survival and metastasis of cancer cells, but the role of B cells in cancer had been controversial,” said Hua Yu, Ph.D., senior author of the paper and Billy and Audrey L. Wilder Professor in Tumor Immunotherapy at Beckman Research Institute of City of Hope. “Some say B cells are tumor promoting, while others report they inhibit cancer. Our paper illustrates that B cells that are CD5-positive — but not CD5-negative — promote tumor growth, and we discovered how CD5 does it — by binding Interleukin-6 (IL-6) and then activating STAT3 tumors-associated B cells.”
The wound that never heals
As Yu explained, STAT3’s evolutionary role is in wound healing: It’s there to stop the body’s natural — and beneficial — immune response to infection, once the healing is complete.
“In the presence of an infection, it’s important for cells to proliferate, for inflammation to provide growth factors and cytokines, and for immune cells to help rebuild,” said Yu. “But, after the infection is taken care of, a feedback loop is necessary to shut down this response.”
The problem is that this process — growth, proliferation, invasion, building new blood vessels, etcetera — is almost identical to cancer.
“Wound healing is self-limiting: Once it’s done, our body knows how to shut it off,” said Yu. “With cancer, however, there are mutations or conditions that keep this process going. Cancer is like the wound that never completely heals.”
CD5: A new partner for IL-6
While its role in tumor growth has been recognized, STAT3 remains an evasive target, including the molecules that may activate it.
As Yu explained with a different metaphor, turning off all the lights in a building is difficult — unless one has the master switch. STAT3 is cancer’s master switch, said Yu. The only problem: It’s buried beneath a dizzying array of cellular circuitry.
“Because there are so many factors in the molecules, it’s difficult to make a precise, effective drug to turn STAT3 off,” said Yu.
Interleukin-6 (IL-6), for example, which stimulates the inflammatory and autoimmune processes in many diseases, is the first molecule known to activate STAT3. While there are drugs that act against the IL-6 pathway, said Yu, they’re not effective in treating many cancer patients.
With their recent discovery that a protein, called CD5, induces STAT3 activation in B cells and T cells following IL-6 stimulation, however, the researchers are closer to understanding — and disrupting — this process.
“Since IL-6 has another way to activate STAT3 — through CD5 — just turning off the IL-6 receptor is not good enough,” said Yu. “That is our new insight into how we can target the IL-6 pathway.”
In other words, even if you get rid of the IL-6 receptor, IL-6 can still function. “IL-6 can go through both its own original receptor and CD5, at least in B cells,” Yu explained.
Moreover, CD5-positive B cells might possess the ability of ‘‘self-amplification’’ through STAT3 activation: Once STAT3 is activated by CD5, it makes additional CD5, which leads to even more CD5, in a self-perpetuating, feed-forward loop. This self-amplification could promote tumor progression by accelerating tumor immunosuppression and angiogenesis, Yu noted.
Now, the researchers are attempting to learn whether one can target CD5 and STAT3 together while continuing to explore the mechanism of the signaling pathway.
As Yu explained, several types of blood tumor cells also highly express CD5. “An important question to examine is how CD5 promotes tumor cell growth and progression by responding to IL-6 and activating STAT3,” she said. “Perhaps we can target CD5 to fight cancer by preventing immune cells from promoting tumor growth.”
It’s been a long journey for Yu and colleagues, whose laboratory was the first to demonstrate that STAT3 could be a target for cancer therapy in vivo while revealing its multiple roles in cancer immunosuppression. Now, after 18 years of chasing a single molecule, the CD5/IL-6 discovery in immune cells brings researchers one step closer to turning off STAT3, the master switch for cancer therapy.
In addition to Chunyan Zhang, Ph.D., and Hua Yu, Ph.D., contributors to this study include City of Hope researchers Paul J. Yazaki, Ph.D., and Zhifang Zhang, Ph.D., and physician-scientists, Stephen J. Forman, M.D., and Larry Kwak, M.D., Ph.D.
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