Immunotherapies have transformed cancer care, but their successes have been limited for reasons that are both complex and perplexing.
In breast cancer especially, only a small number of patients are even eligible to undergo treatment with immunotherapies, and most see little benefit. But in a pre-clinical study researchers outlined a potential way to improve those results by uncloaking breast cancer tumors to the body's immune system.
Publishing in the journal Nature Communications, the researchers identified an enzyme in cells involved in regulating the growth and spread of breast cancers. Testing in mice, they demonstrated a way to shut down the enzyme's activity to allow T-cells to mount an immune attack.
"We found that inhibition of the activity of this enzyme decreased the ability of macrophages in tumors to suppress an immune attack on cancer cells and indeed encouraged them to start producing chemicals that attract more cancer-killing T cells into the tumor," said the senior author. "We can basically uncloak the tumor to the immune system."
Researchers reported that a kinase, or enzyme, called CaMKK2 is highly expressed in macrophages within human breast tumors. Authors also find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets.
Tumor-associated macrophages (TAMs) isolated from Camkk2−/− mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2−/− macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT.
Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment.
"The use of this molecule suppressed tumor growth not only by increasing the accumulation of tumor-killing T cells, but also by reducing the tumor's capability to suppress T cell activity," the senior author said. "It's solving two problems, like we couldn't get into the bar, and if we did, we couldn't get a drink. Now we can do both."
Additional studies are ongoing, with the goal of acquiring data to launch a clinical trial in breast cancer patients within the next 18 months.
Enzyme that suppresses immune system in breast cancer identified!
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