New research led by Sharon R. Pine, PhD, director of the University of Colorado Cancer Center’s Thoracic Oncology Research Initiative, may help doctors understand why some lung cancer patients don’t respond to immunotherapy.
The paper, published in May in the journal Oncogene, examines the role of the transcription factor Sox9 in lung cancers with the KRAS mutation. An error in a protein responsible for normal cell growth, KRAS occurs in around 25% of all lung cancers.
“Sox9 is a transcription factor that’s mostly associated with stem cells,” Pine says. “It regulates cell fate and differentiation, and it’s required for normal development. It was already known that Sox9 is overexpressed in multiple cancer types, including lung cancer, and associated with poor survival in patients with lung cancer. But the mechanisms by which Sox9 drives lung cancer were unknown.”
Using animal models and human lung tumors, Pine and her team found that the overexpression of Sox9 in KRAS-positive lung cancer creates an “immune cold” condition in the tumor, meaning the patient’s immune system is not doing a good job of controlling the cancer. This is why some patients with this mutation don’t respond to immunotherapy, which harnesses the immune system to fight cancer.
“We knocked out Sox9 and it delayed tumor formation, while overexpression of Sox9 accelerated tumor formation,” Pine says. “We went on to explore that mechanism and realized that it had a profound effect on the infiltration of immune cells. We think this is the primary mechanism for how Sox9 was regulating the development of lung cancer.”
Sox9 is a developmental protein that is usually downregulated at birth, but some cancer cells learn how to turn the pathway back on and use it to evade immunotherapy. Eventually, Pine says, lung tumors could be tested for high levels of Sox9 so oncologists could add an immunotherapy drug to counteract its effects.
“The question is, in patients who are treated with immunotherapies, what does Sox9 do?” she says. “Are high levels a biomarker for sensitivity or lack of sensitivity to different immunotherapies?”
The first step in that process is to explore datasets from immunotherapy trials to see how Sox9 expression is associated with response to immunotherapy.
“Our hypothesis is that it offsets the normal process of anti-tumor immunity,” Pine says. “Maybe there's something in that pathway that we can find a new therapy for, to turn the immune system back on.”
Because Sox9 is a transcription factor, she says, its effects are more difficult to target. Further research is needed to find out exactly what Sox9 is regulating in the tumor cell and how that substance can be targeted. She hopes her research results in new options for KRAS-positive lung cancer patients who don’t respond well to the traditional immunotherapy.
“Not every patient responds to immune checkpoint inhibitors,” she says. “By further studying Sox9 we may be able to give them the option of knowing whether they're a good candidate for the currently available immune checkpoint inhibitors, or if we could give them another immunotherapy that would work better for them. There’s a lot of interest in finding accurate biomarkers to guide decisions about immunotherapy.”