Double flipping of killers
Researchers from the Johns Hopkins Cancer Center in the United States report a new mechanism by which breast cancer cells evade the immune system and spread to other areas of the body. If we refine the treatment methods that block this process, it may be possible to stop or prevent metastasis and reduce mortality from breast cancer.
It is known that natural killers (NK) have powerful antitumor and antimetastatic activity. But patients still form metastases, which means that cancer cells have ways to bypass the attack of NK cells. Using a new cell culture method developed by Isaac Chan, one of the authors of the study, the group studied the features of interaction between NK cells and invasive breast cancer cells in vitro in real time. They found that metastatic cancer cells can reprogram NK cells, causing them to stop killing cancer cells and instead help them spread and form metastases. The article also reports on potential immunotherapy strategies that block the reprogramming process in mouse models of metastatic breast cancer.
The study showed that breast cancer cells expressing keratin-14 (the protein that forms the cytoskeleton) and initiating metastasis are vulnerable to NK cells. The authors then found that exposure to cancer cells causes NK cells to lose their cytotoxic function and promote metastatic growth. A comparison of gene expression showed that healthy NK cells have an active molecular phenotype, whereas after contact with cancer cells they resemble dormant NK cells.
Blue cancer cells surrounded by red NK cells. Source: Isaac Chan.
With methods such as molecular profiling and computational analysis in their arsenal, scientists could map every molecular interaction of interest between immune and cancer cells and identify those that probably regulated this connection.
The researchers identified proteins responsible for signaling between NK and tumor cells: T-cell immunoreceptor with Ig and ITIM domains (T cell immunoreceptor with Ig and ITIM domains, TIGIT), leptin-like receptor of killer cells G1 (killer cell leptin-like receptor G1, KLRG1).
As expected, blocking inhibitory signals allowed NK cells not to deplete and continue to attack cancer cells. Thus, treatment with antibodies to TIGIT and KLRG1 receptors or low molecular weight inhibitors of DNA methyltransferases (DNMT) reduced the formation of cancer colonies. The combination of DNMT inhibitors with antibodies further reduces the metastatic potential of breast cancer.
This approach can be used to prevent the formation of metastases, as well as, possibly, to reactivate the immune response to existing metastases.
The researchers note that the targets identified in the work can be used for the treatment of other types of cancer as monotherapy, and as an enhancement of existing immunotherapy methods that stimulate T cells to fight cancer.
Article by I.S.Chan et al. Cancer cells educate natural killer cells to a metastasis-promoting cell state published in the Journal of Cell Biology.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on Johns Hopkins Medicine: Breast Cancer Cells Can Reprogram Immune Cells To Assist In Metastasis.