Natural Killers Cells Hold Promise for Breast Cancer Treatment
By Ruchi Jhonsa, Ph.D.
Natural killer (NK) cells are an essential component of the innate immune system. They possess the ability to kill tumors, antibody-coated cells, or genotoxically changed cells without affecting the healthy ones. Since they don’t require MHC molecule on the cancer cells for activation, they can kill those cells which otherwise would escape detection by T lymphocytes. NK surveillance is, therefore, essential to keep cancers at bay.
However, certain cancers such as breast cancer have been challenging to treat mostly due to their ability to escape NK cell vigilance. It is still a mystery of how breast cancer cells develop resistance to their effects and escape. Now, a group of scientists from Johns Hopkins University has unfurled the mystery behind this by discovering that breast cancer cells can alter the function of natural killer cells, which promotes the spread of breast cancer.
Although metastasizing breast cancer cells are initially vulnerable to NK cell attack, they quickly become immune to their response and start spreading. To understand why this might be happening, the researchers educated the NK cells by keeping them together with cancer cells and later used them on a fresh batch of cancer cells. Interestingly they found that while new NK cells were able to kill cancers easily, the tumor exposed ones failed to do so. Moreover, when the tumor educated NK cells (teNK cells) were injected in mice fostering tumors, they were unable to reduce metastasis of tumors in the body.
These intriguing results set the group to determine how cancer cells might influence NK cells to turn pre-cancerous and if it can be reversed at all. From a series of experiments that determined the RNA profile of normal and teNK cells, it was observed that the latter resembles a resting phase rather than an activated phase of the cell. Besides, they had higher levels of genes, which negatively regulate apoptosis and lower levels of genes that are associated with proliferation, adhesion, and activation of immune responses to tumor cells.
From the bunch of genes identified by the team, two checkpoint inhibitors, TIGIT and KLRG1, were shortlisted for reversing the effects of teNK cells on cancer progression. Both are important checkpoint inhibitors that work towards reducing the function of NK cells and therefore make a vital target for activating teNK cells. Strikingly, treatment with either anti-TIGIT or anti-KLRG1 antibodies brought down the effect of teNK cells and reduced cancer progression.
Besides immune checkpoint inhibitors, the team also found a striking increase in the levels of genes that regulate the chemical signatures on the DNA, the so-called “epigenetic regulators.” DNA methyltransferase, one of the epigenetic regulators, was found highly expressed in teNK cells and, when suppressed using FDA approved DNAMT inhibitors, reduced the effect of teNK cells on cancer growth. However, when DNAMT treatment was combined with anti-TIGIT and anti-KLRG1 antibodies, a drop greater than each of the single treatments was observed in cancer growth.
Lessons to Learn
The high efficiency of anti-PD1 therapies has made them a popular choice amongst patients. However, it is yet to make a mark on breast cancer treatment. Some researchers believe that this is due to the complexity of the breast cancer microenvironment. The key to treating cancer is to understand which pathways are responsible for driving cancer.
The study gives insights about which therapies will be effective and which won’t protect against breast cancer. The authors show that expression of KLRG-1 and DNA methyltransferases is high, and therefore suppressing them using FDA approved therapies against DNA methyltransferase and immunotherapy against KLRG-1 checkpoint inhibitors is effective. Although there was no mention of PD-1/PD-L1 expression in the study, the therapy against these proteins proved useless in breast cancer scenario concurrent with previous clinical studies.
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