Nature recently discovered an immune evasion gene in cancer cells

Summary:

• The researchers found that the expression of immune evasion genes in cancer cells may make cells immune to immunotherapy or develop resistance during treatment;

• In multiple preclinical models, silencing the gene or blocking its expressed protein enhanced the sensitivity of cancer cells to immunotherapy

Immune checkpoint inhibitors are important drugs that boost the immune system's response to various cancers, but some patients' cancer cells are not affected by the drug or develop resistance during treatment
.

Researchers at the Broad Institute of MIT and Harvard at Massachusetts General Hospital (MGH) recently identified an immune evasion gene that is turned on in some of these cells, and they found that silencing the gene enhances the cells' sensitivity
to immunotherapy.

The gene encodes for a protein called TANK-binding kinase 1 (TBK1), a versatile enzyme that plays a recognized role
in coordinating innate immune responses against viruses and other invading pathogens.

In a study published in the journal Nature, a study led by corresponding authors Russell W.
Jenkins, Ph.
D.
, (investigator at the MGH Cancer Research Center, assistant professor of medicine at Harvard Medical School and associate member of the Broad Institute) and Robert T.
Manguso (also investigator at the MGH Cancer Research Center, assistant professor of medicine at Harvard Medical School and associate member of the Broad Institute), It was found that silencing the TBK1 gene enhanced the sensitivity
of cells to immunotherapy.

In addition, in a mouse model of cancer, treatment with a drug inhibitor that blocks the activity of the TBK1 protein overcame tumor resistance to immunotherapy without leading to weight loss or other signs of
systemic toxicity.
This strategy also applies to novel patient-based tumor models, including so-called patient-derived organotypic tumor spheroids (PDOTS), a type of "live slice" containing the patient's own cancer cells and immune cells
.

The team found that, mechanistically, blocking TBK1 could enhance the response
to immunotherapy by sensitizing tumor cells to the effects of immune molecules, including tumor necrosis factor and interferon.

"The deletion of TBK1 enhances immunotherapy, which is counterintuitive because this protein is often thought to promote inflammation
.
Turning it off should reduce the tumor's sensitivity to treatment, not enhance
it.
However, we found that turning off TBK1 reprogrammed tumor cells to respond to cytokine immune signals, causing them to die
.
In this case, the latter effect becomes crucial
.
”

Jenkins said: "Our findings suggest that targeting TBK1 is a novel and effective strategy
to overcome cancer immunotherapy resistance.
Our work also provides a framework for evaluating other potential immune evasion targets in multiple model systems
, using a combination of genetic and pharmacological tools.
”