is a known fact that the human immune system has a natural ability to
identify and attack tumor cells. Innate immune cells that are
particularly effective at killing tumor cells are natural killer (NK)
cells thanks to their ability to secrete cytotoxic enzymes.
However, mutations have allowed many types of tumors to develop a
resistance to NK-mediated killing through ill-defined mechanisms. Dr.
Jerome Ritz and colleagues at the Dana-Farber Cancer Institute in Boston
sought to pinpoint some of these mechanisms using a library of short
hairpin RNAs (shRNA), a type of RNA that binds complementary RNA
sequences in the cell and prevents their transcription into proteins.
His group used a multiple myeloma cell line to screen for genes whose
reduced expression increased susceptibility of the cancer cells to
NK-mediated death. They identified dozens of genes that, when shut down
by shRNA, allowed increased tumor cell killing by NK cells. The
strongest effect was induced by silencing proteins called JAK1 and JAK2,
kinases important for integrating signals from many membrane receptor
proteins. In addition to targeting these kinases by shRNA, the research
team showed that pharmacological inhibition of JAK1 and 2 also increased
tumor cell killing.
Many kinase inhibitors being used or tested today target genes
identified in this screen. The researchers suggest that targeting the
JAK1 and 2 pathways in particular may aid in eradicating tumors that
have developed mechanisms to escape NK cell killing.