July 31: Modern immunotherapy techniques are revolutionizing how we treat cancers, but these treatments still fail in a large amount of patients. The trick to success is finding unique biomarkers that can help our body's natural immune cells home in on, and kill, these evasive tumors. An intriguing new study from Columbia University Irving Medical Center has found that the same gene associated with a condition responsible for autoimmune-related hair loss could be recruited to help our immune cells better target tumors.
The inspiration behind this new research came from the hypothesis that the same characteristics prominent in autoimmune disease could be exploited to better battle cancer, which is known for its extraordinary ability to avoid our immune system.
"We should be able to identify genetic signals that are hyperactive in autoimmune disease, and then harness those signals in tumors that have developed a way to avoid the immune response," says James Chen, lead author in this study.
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When a foreign substance, such as a germ or bacteria, enters the body, our T-cells immediately step up into action. These are our defender cells, geared to multiply and attack when needed. In the instance of an autoimmune disease, our T-cells can be dysfunctionally overproduced and kill healthy cells.
An early part of this new research found that a particular gene called IKZF1, was responsible for an overproduction of T-cells in an autoimmune disease called alopecia areata, where immune cells destroy healthy hair follicles. While this over expression of IKZF1 acts as a kind of bullseye, attracting killer T-cells to a target, the researchers wondered if the same gene could be expressed in tumors, so as to help immune cells better home in on those cancerous targets.
A computer algorithm was developed allowing the researchers to scan the Cancer Genome Atlas and find specific tumor types with this particular gene in their regulatory networks. A variety of cancers were successfully found suspected to be positively sensitive to the IKZF1 gene, including melanoma and prostate cancers.
In subsequent animal experiments, the researchers genetically modified certain tumors to overexpress the IKZF1 gene. It was found that by doing this the tumors were much more responsive to immunotherapy treatments. Essentially, the tumors became much more visible to the killer T-cells on the hunt.
"Clinically, this is an especially exciting finding, since prostate cancer is generally very poorly infiltrated by immune cells. Turning these 'cold' tumors 'hot' could be a key to therapeutic success," says co-author on the study, Charles Drake.
Interestingly, the algorithm the team developed was also able to predict which cancers would not benefit from an increase in the IKZF1 gene. Colorectal and kidney tumors for example, did not contain any inherent IKZF1 gene activity, meaning this particular gene could not be exploited as a way to help immune cells target these cancers.
Any realistic therapeutic outcome from this research is probably several years away as there currently isn't any clear way to specifically activate the IKZF1 gene in human tumors. A more immediate outcome however, is that testing specific tumor biopsies for IKZF1 gene activity may be an effective way to learn how likely a patient will be to respond to current immunotherapies. A study of data from human melanoma patients did reveal that tumor samples with disabled IKZF1 gene activity corresponded with worse survival outcomes compared to other melanoma patients. This confidently suggests that IKZF1 may be a good indicator of whether a tumor is more or less likely to evade our immune system attacks.
The new research was published in the journal Cell Systems.
