Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells.
Natural killer (NK) cells are primary effectors of innate immunity directed against transformed tumor cells. In response, tumor cells have developed mechanisms to evade NK cell-mediated lysis through molecular mechanisms that are not well understood. In the present study, we used a lentiviral shRNA library targeting more than 1,000 human genes to identify 83 genes that promote target cell resistance to human NK cell-mediated killing. Many of the genes identified in this genetic screen belong to common signaling pathways; however, none of them have previously been known to modulate susceptibility of human tumor cells to immunologic destruction. Gene silencing of two members of the JAK family (JAK1 and JAK2) increased the susceptibility of a variety of tumor cell types to NK-mediated lysis and induced increased secretion of IFN-γ by NK cells. Treatment of tumor cells with JAK inhibitors also increased susceptibility to NK cell activity. These findings may have important clinical implications and suggest that small molecule inhibitors of tyrosine kinases being developed as therapeutic antitumor agents may also have significant immunologic effects in vivo.
Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA. Roberto_Bellucci@dfci.harvard.edu
Roberto
R
Bellucci
Hong-Nam
HN
Nguyen
Allison
A
Martin
Stefan
S
Heinrichs
Anna C
AC
Schinzel
William C
WC
Hahn
Jerome
J
Ritz
D017209:Apoptosis; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism; D019139:Tumor Escape / Q000235:genetics*; D020032:Tyrphostins / Q000494:pharmacology
D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D007371:Interferon-gamma; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C070139:TYK2 protein, human