Inflammation is a normal way of healing after injury or illness. But if it becomes chronic, even low-level inflammation can promote cancer. The underlying mechanisms are not completely understood, but a new faculty member at The University of Texas Southwestern Medical Center hopes to learn more by studying chronic inflammation at the molecular level.
Immunologist Zhenyu Zhong was recruited to UT Southwestern in 2018 from the University of California, San Diego, where he was a postdoctoral researcher, with the help of a First-Time Tenure-Track Award from CPRIT.
Inflammation is a body’s normal response to injury or damage, and restores health through tissue repair and regeneration. Immune therapy, which ramps up a body’s own immune system using T-cells to kill cancer, has become a promising cancer treatment.
So it may seem counterintuitive that the immune system can also promote cancers, but chronic low-level inflammation is probably the true culprit behind many cancer risk factors, including aging, alcohol overconsumption, and obesity.
“These are the bright and dark sides of the immune system,” Zhong says. “There is no doubt that killing tumor cells with invigorated T-cells is a superb way to treat cancer. On the other hand, if we have a chronic version of the immune response, this will promote instead of limit cancer.” Zhong is taking a particularly close look at obesity, which is most relevant in the state of Texas. After aging, it is the number two risk factor for cancer.
At the molecular level, Zhong wants to know how chronic immune response begins, continues, and eventually promotes cancer. The culprits appear to be immune signaling molecules, called cytokines. Mutated cells actually require a signal sent by the cytokines in order to survive, thrive, and become cancerous.
He’s found that mitochondria, the powerhouses of cells, serve as signaling hubs that control inflammation. Mitochondria convert oxygen and nutrients into the fuel that runs most cellular processes. But they also seem to drive immune system activation, and how they behave in an immune cell determines whether the cell will be activated or remain silent.
Obesity can lead to persistent low-level inflammation in the liver, and by accumulating pro-inflammatory cytokines, can promote the genesis and survival of pre-cancerous cells. Chronic liver disease induced by obesity begins with fatty liver disease, progresses to non-alcoholic hepatitis, and finally to its end stage, liver cancer.
“When you have non-alcoholic hepatitis or fatty liver disease, those patients are at high risk for developing obesity-associated liver cancer,” Zhong says. He wants to find the molecule responsible for triggering the mitochondria’s inflammatory response. “If we know what molecule is relevant, we can stop the disease at the fatty liver stage, without progressing into inflammation, or stop it at the next stage and prevent cancer,” he says.
He’s also hoping to find out why 20 percent of patients who receive immune therapy for liver cancer are cured of their disease, while most don’t respond at all. He hopes that reducing chronic inflammation would make immune therapy more effective, maybe through combination therapy.
Zhong credits the world-class, supportive, and cohesive scientific environment at UT Southwestern. “It’s amazing that we have the resources to do something that we could hardly imagine, because of the funding environment and strength here,” he says. “We rely highly on experimental mice, which are not inexpensive to maintain, and we’re very grateful for the support of the university and the state.”
Zhong completed his undergraduate studies in biology at Hebei University in China and received his Ph.D. in immunology from Loyola University Chicago. He joined UCSD as a postdoctoral fellow in 2013, studying inflammation and tumor immunology.
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